Molecular Subtype-Specific Breast Cancer Organoids: Development of an FGF-Free Estradiol Valerate Culture System for Precision Drug Screening

Molecular Subtype-Specific Breast Cancer Organoids: Development of an FGF-Free Estradiol Valerate Culture System for Precision Drug Screening | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Molecular Subtype-Specific Breast Cancer Organoids: Development of an FGF-Free Estradiol Valerate Culture System for Precision Drug Screening Chunyan Zhang, Bing Han, Zhihua Jia, Min Liu, Yanxia Li, Jie Xu, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6906829/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 08 Jan, 2026 Read the published version in Cancer Cell International → Version 1 posted 10 You are reading this latest preprint version Abstract Breast cancer, a prevalent malignancy among women, exhibits high heterogeneity, highlighting the critical need for personalized treatment strategies. Breast cancer organoids (BCOs), an emerging in vitro research tool, closely mimic the biological characteristics of tumors and demonstrate distinct differences in therapeutic response, prognosis, and biological features. However, the incomplete culture system of BCOs is still a challenging aspect of current research. In order to further optimize the existing culture formula of BCOs, we collected tumor tissue samples from breast cancer patients with various molecular subtypes, including Luminal A, Luminal B, HER2 overexpressing (HER2 + ), and triple-negative breast cancer (TNBC). The samples were extracted and cultured using commercially available media. We observed that some media failed to sustain the growth of breast cancer organoids, while others, although supporting organoid survival, led to the loss of parental molecular subtype characteristics in most cases. Through literature review and screening of key factors, we developed an FGF-free estradiol valerate (EV) culture system. Using triple-positive breast cancer samples, we optimized the concentration of EV. Our results indicated that 0, 10, and 20 µM EV maintained normal organoid growth, whereas 50 µM EV promoted adherent differentiation, which is detrimental to long-term organoid culture. Further analysis revealed that 20 µM EV not only preserved the organoid cellular morphology but also retained the parental molecular subtype features. Using this optimized culture system, we successfully cultivated breast cancer organoids from TNBC, Luminal, and HER2 + samples. We then developed a drug sensitivity prediction model using our established organoid culture system, which included triple-negative, Luminal, and HER2-positive breast cancer subtypes. By comparing imaging data before and after clinical treatment, we found a high concordance between drug sensitivity in the organoid model and clinical efficacy. This study provides an optimized culture medium system for the cultivation of breast cancer organoids and validates its potential application in precision drug screening. This model promises to deliver precise and effective treatment strategies for breast cancer patients, further improving their prognosis and quality of life, and ushering in a new chapter in personalized breast cancer treatment. Breast Cancer Organoids Molecular Subtypes FGF-Free Culture System Estradiol Valerate Precision Drug Screening Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 1 Introduction Breast cancer is a malignant tumor with the highest incidence and mortality rates of cancer among women globally [ 1 ] . The clinical management of breast cancer is challenging because of tumor heterogeneity [ 2 ] . Breast cancer is classified by the expression of molecular markers such as estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67 into several subtypes, including Luminal A, Luminal B, HER2-positive, and triple-negative breast cancer (TNBC). Each subtype exhibits distinct responses to chemotherapy, endocrine therapy, and targeted drugs [ 3 ] . In recent years, advancements have been made in precision medicine for individualized treatment strategies on the basis molecular subtyping [ 4 ] , driven by the use of preclinical models, such as cell lines and patient-derived xenograft models. However, these models do not accurately mimic the tumor microenvironment and retain molecular subtype characteristics of the parental tumor, leading to discrepancies between drug response predictions and clinical outcomes [ 5 ] . In recent years, patient-derived tumor organoid (PDO) models have demonstrated immense potential and application value in cancer research and drug development. PDOs are three-dimensional cell structures cultivated from tumor cells isolated from patient tissue under specific conditions in vitro. PDOs highly recapitulate the growth environment of the original tumor within the human body, preserving phenotypic, genotypic, and heterogeneous features of the parental tissue. This unique feature makes PDOs an ideal tool for studying tumor biology, exploring drug action mechanisms, and assessing drug efficacy [ 6 ] . Multiple studies have indicated marked differences in the drug responses among PDOs derived from different molecular subtypes of breast cancer. These differences include sensitivity to chemotherapeutic agents and the responses to therapeutic approaches such as endocrine therapy and targeted therapy [ 7 ] . For instance, certain drugs are effective against Luminal A breast cancer PDOs but ineffective against TNBC PDOs, and vice versa, where some drugs demonstrate therapeutic effects on TNBC PDOs but are ineffective against Luminal A breast cancer PDOs. This variability in drug responses provides invaluable clues and evidence for formulating personalized treatment plans. Despite the significant progress in breast cancer PDO research, the current PDO culture system faces two major limitations. First, most existing media rely on exogenous growth factors like fibroblast growth factor (FGF), which may lead to loss of subtype characteristics or phenotypic drift [ 8 ] . Second, the lack of standardized culture protocols for different molecular subtypes results in low establishment success rates and insufficient stability of PDOs from aggressive subtypes such as TNBC. These issues severely limit the translational application of PDOs in precision medicine [ 9 – 11 ] . To address these challenges, we developed an FGF-free estradiol valerate (EV) optimized culture system, aiming to overcome the barriers to maintaining molecular subtypes in traditional media. By systematically analyzing the growth requirements of PDOs from Luminal B, HER2-positive, and TNBC subtypes, we demonstrate for the first time that 20 µM EV can replace FGF to sustain organoid proliferation while preserving key molecular features such as ER/PR/HER2 expression profiles and Ki-67 index. Further integration of drug sensitivity testing across PDOs of multiple breast cancer subtypes with clinical efficacy data validation provides a high-fidelity experimental model for individualized breast cancer treatment decisions. This approach is poised to facilitate a paradigm shift from “empirical treatment” to “molecular subtype-driven therapy,” thereby enhancing patients’ quality of life and initiating a new chapter in personalized treatment for breast cancer. 2 Materials and Methods 2.1 Ethics Statement and Patient Consent The human breast cancer samples analyzed in this study were derived from patients with clinically distinct molecular subtypes. Detailed clinical information for each patient is provided in Table 1 . The study protocol was reviewed and approved by the Institutional Review Board (IRB) of Tianjin Fifth Central Hospital (Approval No. WZX-EC-KY2024036) and complied with the Declaration of Helsinki principles. Patient samples were obtained after we obtained informed consent. Table 1 2.2 Processing and Isolation of Breast Cancer Tissue Samples Breast cancer tissue samples were collected from fresh, surgically resected tumor tissues within 30 min post-resection. The samples were rinsed twice with sterile saline solution to remove adherent blood and surface contaminants. Cancerous tissues and adjacent normal control tissues were sampled, carefully avoiding areas with hemorrhage or necrosis. The sampled tissues were promptly placed in tissue preservation solution (bioGenous, Suzhou, China) and transported to the laboratory under low-temperature conditions. These steps were performed by professional pathologists. The collected tumor and normal breast samples underwent further processing in a sterile biosafety cabinet. The samples were rinsed twice with pre-cooled sterile Hank's Balanced Salt Solution (HBSS, Pricella, Wuhan, China). Sterile ophthalmic scissors were used to carefully remove unwanted tissues such as fat. The tissues were divided into three parts. One part was rapidly frozen in liquid nitrogen and stored at -80°C for molecular biology and biochemical analyses. Another part was fixed with 4% paraformaldehyde for morphological observation and analysis. The remaining part was used for the culture of breast cancer organoids. For the breast cancer tissues intended for organoid culture, sterile ophthalmic scissors were used to cut the tissues into small cubes of approximately 1 mm³. The tissue pieces were added to a container containing tissue digestion solution (Accurate International, Guangzhou, China) and placed in a 37°C shaking incubator for approximately 15–30 min. Once most of the cell clusters were dissociated, the reaction was terminated with HBSS solution. The digested tissue suspension was filtered through a 100 µm cell strainer. The filtrate was centrifuged at 180 ×g for 3 min, and the supernatant was discarded. The cell pellet was washed with HBSS solution and centrifuged again. The pellet was resuspended in Matrigel matrix (Corning, New York, US) and approximately 30–50 µl of the cell suspension was added to each well of a 37°C preheated 24-well plate. The plate was inverted and placed in a constant-temperature CO₂ cell culture incubator. Once the Matrigel solidified, different formulations of breast cancer organoid medium were added to each well for culture. 2.3 Cultivation, Passage, Cryopreservation, and Revival of Breast Cancer Organoids Breast cancer organoids were cultured, and fresh medium was replaced every 2 days. When the organoids reached a diameter of approximately 200 µm and exhibited good growth status, they were passaged. The medium was discarded, and the organoids were gently washed with PBS. The organoids were digested with a specialized organoid digestion solution (bioGenous) to disperse them into small cell clusters. The cells were collected by centrifugation and inoculated into fresh Matrigel at a specific ratio for continued culture. When the breast cancer organoids grew and reached a diameter of approximately 200 µm, they were frozen for long-term preservation. First, the Matrigel encapsulating the organoids was disrupted using a pipette tip, and a cell recovery solution (Corning) was added to remove the Matrigel components. The organoid cell clusters were collected by centrifugation, resuspended in organoid cryopreservation medium (bioGenous), and transferred to cryogenic vials. The vials were placed in a programmed freezing container and stored at -80°C overnight before being transferred to a liquid nitrogen tank for long-term preservation. For the thawing of breast cancer organoids, a method similar to that used for 2D cell lines was used. The frozen organoids were retrieved from the liquid nitrogen tank and rapidly thawed in a preheated 37°C water bath. The thawed cells were collected by centrifugation and resuspended in Matrigel before being inoculated into 24-well plates at a specific density for subsequent culture. 2.4 Histology and Immunohistochemistry The tissues were fixed in 4% paraformaldehyde overnight, followed by dehydration and embedding in paraffin. Organoids were stained with eosin, pre-embedded in 3% agarose gel, and fixed in 4% paraformaldehyde for 30 min. Staining was conducted 4 µm-thick paraffin sections. Following routine dewaxing and hydration, H&E staining was performed using standard methods. The sections were then subjected to histopathological evaluation. For immunohistochemical staining, sections were subjected to citrate high-pressure retrieval at pH 6.0 (ZSGB-BIO, Beijing, China). Staining was performed using a two-step universal kit (ZSGB-BIO, PV8000). The primary antibodies included Ki-67 (ZSGB-BIO), anti-ER (ZSGB-BIO,), anti-PR (ZSGB-BIO), and anti-HER2 (Roche, Basel, Switzerland), all diluted to specific ratios. Images were captured using an Olympus microscope. Semi-quantitative analysis of immunostaining was performed by certified pathologists using the H-score system as follows: H-score (range 0–12) = proportion of positive cells (0–4 points) × staining intensity (0–3 points). 2.5 Drug Sensitivity Analysis We first reviewed the medication history and imaging data of breast cancer patients with different molecular subtypes and conducted an in-depth analysis of the impact of various medication regimens on the disease progression in conjunction with pathological diagnoses and imaging records. We then assessed the sensitivity of patients to different drugs. Breast cancer organoids of different molecular subtypes were digested, uniformly seeded into 96-well plates at a density of 3000 cells per well, and grown to a stable state. Organoids were treated with different concentrations of drugs such as Carboplatin (0.01-50 µM), Paclitaxel (0.001-50 µM), Doxorubicin (0.01–100 µM) and Cyclophosphamide (0.01–200 µM), which commonly used in the clinical setting for patients with different molecular subtypes of breast cancer for approximately 48 h. Cell viability was evaluated using the Alamar Blue™ Cell Viability Assay Kit (Invitrogen, Carlsbad, CA, USA) and a microplate reader (Molecular Devices, California, US). We plotted the IC50 curves for each drug group and calculated the corresponding cell viability values. 3 Results 3.1 Construction of Breast Cancer Organoids with Different Molecular Subtypes Using Commercially Available Media A schematic diagram to illustrate the construction of the breast cancer organoid system is shown in Fig. 1 A. We first evaluated the efficacy of four commercial media (from Manufacturers A–D) in generating breast cancer organoids from Luminal A, Luminal B, HER2-positive, and triple-negative breast cancer (TNBC) samples ( Supplementary Fig. 1 ). The medium from Manufacturer A was largely ineffective in forming organoid spheres. While media from Manufacturers B and C induced the formation of organoid spheres in the short term, structural collapse occurred on day 36 and day 54, respectively. The medium from Manufacturer D was able to stably maintain the growth of all subtype organoids, with a success rate exceeding 90%. The formed organoids were transparent, solid spherical structures with good growth status, and they maintained morphological stability after four consecutive passages. In freeze-thaw experiments, only the growth of HER2-positive organoids was slightly compromised, while organoids of other molecular subtypes maintained robust growth (Fig. 1 B). These results showed that the medium from Manufacturer D can effectively support the long-term expansion, culture, and cryopreservation of breast cancer organoids across different molecular subtypes. 3.2 Molecular and Histopathological Discordances in above Commercially Cultured Breast Cancer Organoids We next systematically evaluated the morphological and molecular marker consistency between the breast cancer organoids constructed using commercially available media and their parental tumor tissues. Paraffin sections of the organoids were subjected to H&E staining and immunohistochemical analysis (Fig. 2 ). H&E staining results demonstrated that the organoids of all molecular subtypes effectively recapitulated the cell morphology and histological features of parental tissues, including nuclear enlargement, hyperchromasia, and glandular or solid growth patterns. However, immunohistochemical analysis revealed slightly elevated Ki67 expression in organoids compared with parental tissues, along with a pronounced subtype-dependent molecular marker deviation. Except for the stable maintenance of ER/PR/HER2 triple negative phenotype in TNBC organoids (with a 100% compliance rate), all other subtypes exhibited abnormal expression of characteristic molecular markers ER/PR/HER2 (immune score dropped to 0) ( Supplementary Fig. 2 ). These findings indicate that while the commercially available culture medium systems can support the morphological maintenance and expansion of breast cancer organoids in vitro, they struggle to stably preserve the expression profiles of key biomarkers specific to each molecular subtype during long-term culture. 3.3 The Effect of FGF-free Conditions Combined with EV on the Breast Cancer Organoid Systems On the basis of prior bioinformatics screening, we selected HER2-positive (HR-positive) breast cancer samples with positive molecular markers and evaluated the impact of FGF and different estrogen forms (estradiol (ES)/estradiol valerate (EV)) on the stability of molecular characteristics in breast cancer organoids. FGF supplementation significantly impaired organoid growth, inhibiting three-dimensional proliferation (Day 6 diameter: 195 ± 22 µm vs. 325 ± 28 µm in the FGF-free group, P < 0.01) and inducing adherent differentiation in more than half of the organoids (Fig. 3 A–B), likely attributable to FGF activity. To compare the effects of ES and EV on breast cancer organoids, we used P5 organoids. Bright-field microscopy and HE staining revealed no significant differences in organoid spheroid morphology, size, or optical transparency between the two groups (Fig. 3 C–D). Immunohistochemical staining demonstrated that compared with the EV group, in the ES group, the ER/PR expression was nearly lost by passage 5; this is likely because of the short metabolic half-life of ES (< 48 h in vitro activity maintenance). In contrast, the EV group maintained stable ER + /PR + phenotype through esterified sustained-release properties, showing high consistency with primary tumors after 5 passages (Fig. 3 D–E). These findings suggest that the FGF-free culture system combined with EV can concomitantly mitigate FGF-induced mesenchymal transition and ES metabolic impairment. 3.4 Screening of EV concentrations in breast cancer organoids of distinct molecular subtypes To investigate the optimal EV concentration for the EV culture system, we carefully selected HER2-positive (HR-positive) breast cancer samples with positive molecular markers and cultured them in media supplemented with 0–50 µM EV. The results of the bright-field showed that the 50 µM group showed restricted proliferation and adherent differentiation, while the 0–20 µM groups maintained typical 3D spheroidal growth. H&E staining demonstrated that all groups maintained the histological architecture and nuclear atypia of primary tumors (Fig. 4 A). Semi-quantitative immunohistochemical analysis demonstrated that ER/PR/HER2 positivity in the 20 µM and 50 µM groups closely matched those of primary tumors, while the 0 µM and 10 µM groups exhibited complete loss of these markers. Additionally, the Ki67 proliferation index was comparable or even higher in organoids than that in primary tumor tissues (Fig. 4 A–B). Collectively, these findings indicate that 20 µM estradiol valerate-containing medium achieves an optimal balance between organoid proliferative activity and molecular phenotype stability, providing critical culture parameters for constructing molecular subtype-specific breast cancer models. 3.5 Application of FGF-Free + EV (20 µM) Culture System in Various Molecular Subtypes of Breast Cancer Organoids Using the FGF-free + 20 µM EV culture system, we successfully established organoid models of triple-negative breast cancer, Luminal, and HER2 + breast cancer. After 10 days of three-dimensional culture, organoids of all three subtypes developed translucent, solid spherical structures, maintaining > 90% morphological stability even after five passages. H&E staining demonstrated that the organoids preserved the cellular morphological and structural characteristics of the primary tumors (Fig. 5 A–C). Semi-quantitative immunohistochemical analysis confirmed that all organoids retained their parental molecular characteristics: the TNBC group showed 100% concordance with triple-negative status tissue, while Luminal A and HER2 + (HR + ) organoids expressed their respective characteristic molecular markers, along with slightly reduced IHC scores (Fig. 5 D). This confirms the development of a system that overcomes the limitations of conventional media that lead to loss of subtype-specific features. 3.6 The Relationship between Personalized Drug Sensitivity Testing in Breast Cancer Organoids of Different Molecular Subtypes and Real-World Patient Treatment Efficacy We retrieved preoperative medication regimens and imaging data from clinical patients corresponding to the successfully generated triple-negative breast cancer, Luminal, and HER2 + breast cancer organoid models. Drug sensitivity testing was performed in these organoid models, and the results were compared with the changes in tumor lesions observed in the imaging data of clinical patients before and after treatment. CT imaging results of TNBC patients showed a significant reduction in tumor lesions after 6 cycles of combined treatment with paclitaxel (albumin-bound) and carboplatin. Drug sensitivity testing in TNBC organoid models revealed the strongest sensitivity to carboplatin, followed by paclitaxel, while anthracycline doxorubicin exhibited the poorest efficacy, consistent with the clinical sensitivity of patients to the ACT regimen (Fig. 6 A). Ultrasound results of Luminal A patients demonstrated a 27.2% reduction in the maximum tumor area after 6 cycles of ACT treatment, indicating a certain degree of sensitivity. Similarly, drug screening in organoid models showed the strongest sensitivity to paclitaxel, while cyclophosphamide and doxorubicin had no significant efficacy, aligning with the clinical sensitivity of patients to the treatment regimen (Fig. 6 B). Ultrasound results of HER2 + (HR + ) patients revealed almost no change in tumor volume after 4 cycles of TCbHP treatment (paclitaxel (albumin-bound) + carboplatin + trastuzumab + pertuzumab), suggesting a certain degree of drug resistance. Consistent with these results, drug screening in organoid models showed poor sensitivity to paclitaxel, carboplatin, and trastuzumab, matching the drug resistance observed in clinical patients (Fig. 6 C). These results demonstrated that the drug sensitivity results of breast cancer organoids with different molecular subtypes were generally consistent with real-world clinical outcomes, indicating that this model can accurately guide the selection of personalized treatment regimens and provide experimental evidence for the translation of precision medicine in breast cancer. 4 Discussion Breast cancer, a highly heterogeneous disease, necessitates personalized treatment strategies tailored to its molecular subtypes. Breast cancer is categorized into subtypes on the basis of hormone receptor (ER, PR) and HER2 expression status such as Luminal A, Luminal B, HER2-positive, and triple-negative, each exhibiting distinct biological behaviors and therapeutic responses [ 12 ] . This molecular heterogeneity significantly complicates clinical management. For instance, luminal breast cancers generally respond well to endocrine therapy, whereas triple-negative breast cancers are treated with chemotherapy and targeted therapies. However, even within the same molecular subtype, patient responses to treatment vary considerably, further increasing the challenges of clinical intervention. Therefore, developing experimental models capable of mimicking tumor heterogeneity and predicting therapeutic responses has become an urgent need in current breast cancer research [ 13 ] . In recent years, organoid models have emerged as a novel in vitro research tool. Organoids effectively preserve the molecular characteristics and heterogeneity of parental tissues and have become a powerful tool for studying tumor biology, drug sensitivity, and personalized medicine [ 14 ] . However, the efficacy of organoid culture systems heavily relies on the optimization of culture conditions, particularly the selection of media and growth factors, which remains a key challenge in this field. Through systematic screening of commercially available media, our study revealed that most media struggled to sustain the long-term growth of breast cancer organoids, with organoids tending to lose the molecular subtype features of their parental tissues during culture. Consistent with previous reports [ 15 ] , we observed that Manufacturer A’s medium was largely ineffective in promoting organoid formation across tested samples, underscoring the crucial role of specific growth factor combinations in organoid initiation and maintenance. While the media from Manufacturers B and C induced organoid formation in the short term, they exhibited certain limitations in maintaining long-term organoid survival and functional integrity. In contrast, Manufacturer D’s medium demonstrated superior performance, enabling robust organoid formation and stable growth across all molecular subtypes with a success rate exceeding 90%. These findings align with a growing body of literature emphasizing the importance of defined serum-free medium formulations in preserving the genetic and phenotypic stability of cancer organoids [ 11 , 16 ] . By comparing the growth status and molecular marker expression of organoids under different media, our study further confirmed and elucidated the limitations of existing media in maintaining the molecular subtype features of breast cancer organoids. Despite organoids retaining tumor cell morphology when cultured in Manufacturer D’s medium, immunohistochemical analysis revealed a loss of subtype-specific molecular markers in Luminal A, Luminal B, and HER2-positive organoids after passaging. This observation is consistent with previous studies reporting similar challenges in maintaining molecular fidelity during long-term organoid culture [ 17 ] . Notably, TNBC organoids exhibited remarkable stability in preserving their triple-negative phenotype, suggesting that the molecular mechanisms underlying subtype stability may vary across different cancer subtypes. The increased Ki67 expression in organoids compared with parental tumors may be attributed to the enrichment of breast cancer stem cells in vitro. These findings highlight the necessity for further optimizing culture conditions. Breast cancer with HER2 overexpression is a clinically aggressive subtype associated with poor prognosis. Notably, approximately 50% of HER2 + tumors co-express hormone receptors (HR), constituting a distinct molecular subtype characterized by dual positivity for HER2 and estrogen/progesterone receptors. We next obtained HER2 + /HR + patient-derived tumor samples and evaluated the impact of FGF and estrogen supplementation on maintaining the phenotypic stability of organoid cultures. Our data indicated that FGF supplements, commonly used in organoid culture protocols, significantly impaired organoid growth and induced adhesion, likely as a result of pro-differentiating effects. This finding aligns with recent reports that FGF promotes cell proliferation by activating MAPK and PI3K/AKT signaling pathways, but its overactivation may lead to the loss of original molecular features in organoids [ 18 ] . Estradiol and EV, both estrogen analogs, play crucial roles in the growth and differentiation of breast cancer cells [ 19 ] . The long-acting estrogen derivative EV demonstrated superiority over estradiol in maintaining ER/PR expression across multiple passages. This observation can be attributed to the esterified form of EV, which provides sustained release of bioactive estrogen, thereby overcoming the rapid metabolic clearance of estradiol in vitro. Our data support the notion that EV supplementation can effectively preserve hormone receptor expression in ER-positive breast cancer organoids, as previously reported in other model systems [ 20 ] . On the basis of the above findings, we further optimized the EV concentration in the FGF-free culture system and determined that 20 µM was the optimal concentration for balancing organoid proliferation and molecular phenotype stability. This concentration not only supported robust organoid growth but also preserved the subtype-specific molecular features of HER2 + (HR + ) organoids. This finding is consistent with the study by Hortobagyi [ 21 ] , who demonstrated that estrogen exerts dose-dependent effects on breast cancer cell proliferation and differentiation by activating ERα and ERβ signaling pathways. Low concentrations of estrogen primarily promote cell proliferation through ERα, while high concentrations may induce cell differentiation through ERβ or non-classical signaling pathways such as PI3K/AKT and MAPK. Additionally, high concentrations of EV may further influence organoid growth patterns by altering the composition or stiffness of the extracellular matrix (ECM) [ 22 ] . These mechanisms provide a theoretical basis for the role of EV in breast cancer organoid culture and offer new directions for future medium optimization. To validate the reliability of the FGF-free EV culture medium system, we conducted cultivation assays using breast cancer samples of distinct molecular subtypes: triple-negative, Luminal, and HER2-positive. All three subtypes exhibited sustained growth, maintained robust morphological integrity, and preserved the molecular specificity characteristic of their parental tissues. These findings underscore the superior performance of this novel medium system in supporting the long-term expansion of organoids derived from diverse breast cancer molecular classifications. In recent years, chemotherapy has emerged as a cornerstone in the multimodal treatment of breast cancer, particularly within the context of neoadjuvant therapy. As outlined in the Expert Consensus on Neoadjuvant Therapy for Breast Cancer and international St. Gallen guidelines, chemotherapy regimen selection must adhere to the precision medicine paradigm of “molecular subtyping-efficacy prediction.” We next developed a drug sensitivity prediction model using our established organoid culture system, which included triple-negative, Luminal, and HER2-positive breast cancer subtypes. This innovative approach establishes a correlation validation framework between organoid responses and patient treatment outcomes. Our data demonstrated a notable consistency between drug responses in organoids of different cancer subtypes and clinical outcomes. TNBC organoids exhibited higher sensitivity to carboplatin, reflecting significant tumor regression observed in patients receiving ACT regimens [ 23 ] . Similarly, Luminal A organoids showed the highest sensitivity to paclitaxel, correlating with modest tumor reduction in patients receiving the same treatment [ 24 ] . HER2-positive organoids demonstrated poor sensitivity to TCbHP, which indicated a lack of response in patients. These findings are consistent with previous studies demonstrating the predictive value and potential applications of cancer organoids in patient drug responses [ 25 ] . In conclusion, our study emphasizes the critical importance of medium optimization in establishing high-fidelity cancer organoid models that accurately reflect the molecular and functional features of parental tumors. The FGF-free + EV culture system introduced in this paper represents an advancement in breast cancer organoid technology, providing a foundation for drug discovery, biomarker development, and personalized treatment planning. Despite the significant findings described here, this study has several limitations. First, the sample size was small and did not cover all breast cancer molecular subtypes; future studies should expand the sample size and explore culture conditions for other subtypes. Second, this study did not delve into the mechanisms underlying the role of EV in organoid culture; future research should pursue multi-omics technologies (such as transcriptomics and proteomics) for systematic analysis. Furthermore, optimization of other medium components (such as growth factors and Matrigel) [ 26 ] warrants further investigation. In the future, we will focus on exploring medium components and mechanisms of action, optimizing culture conditions to enhance the molecular stability of organoids, expanding the scope of tested drugs to cover emerging therapies, and validating the clinical utility of organoid-based drug sensitivity testing in prospective clinical trials. Declarations Ethical Approval and Consent to participate This study followed the Declaration of Helsinki and received ethical approval from the Tianjin Fifth Central Hospital IRB (Approval No.: WZX-EC-KY2024036, Date: 06/27/2024). All participants provided written informed consent. Consent for publication All authors have reviewed and approved the final manuscript for publication, confirming its accuracy and originality. Availability of supporting data The data that support the findings of this study are available in the Manuscript and Additional files of this article. Competing interests The authors declare that they have no competing interests. Funding This study was supported by grant from Tianjin Municipal Education Commission's research project (2023KJ121). Authors' contributions Chunyan Zhang: Methodology, Validation, Writing-original draft, Project administration. Bing Han: Methodology, Validation. Zhihua Jia: Resources. Min Liu: Validation. Yanxia Li: Formal analysis. Jie Xu: Formal analysis. Jie Zheng: Validation. Yajing Sun: Validation. Yuting Le: Resources. Shupeng Zhang: Writing-original draft. Zhijiang Shao: Data curation. Jian Wang: Writing-review and editing. Xiaozhi Liu: Conceptualization. Acknowledgements We thank Gabrielle White Wolf, PhD, from Liwen Bianji (Edanz) (www.liwenbianji.cn) for editing the English text of a draft of this manuscript. 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Nucleic Acids Res . 2022;50(20):11492-11508. doi:10.1093/nar/gkac908 Saha Roy S, Vadlamudi RK. Role of estrogen receptor signaling in breast cancer metastasis. Int J Breast Cancer . 2012;2012:654698. doi:10.1155/2012/654698 Plichta JK, Thomas SM, Hayes DF, et al. Novel Prognostic Staging System for Patients With De Novo Metastatic Breast Cancer. J Clin Oncol . 2023 May 10;41(14):2546-2560. doi: 10.1200/JCO.22.02222. Epub 2023 Mar 21. PMID: 36944149; PMCID: PMC10414698. Bissell MJ, Hines WC. Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat Med . 2011;17(3):320-329. doi:10.1038/nm.2328 Lin C, Cui J, Peng Z, et al. Efficacy of platinum-based and non-platinum-based drugs on triple-negative breast cancer: meta-analysis. Eur J Med Res . 2022;27(1):201. doi:10.1186/s40001-022-00839-0 Saha Roy S, Vadlamudi RK. Role of estrogen receptor signaling in breast cancer metastasis. Int J Breast Cancer . 2012;2012:654698. doi:10.1155/2012/654698 Vlachogiannis G, Hedayat S, Vatsiou A, et al. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science . 2018;359(6378):920-926. doi:10.1126/science.aao2774 Gjorevski N, Sachs N, Manfrin A, et al. Designer matrices for intestinal stem cell and organoid culture. Nature . 2016;539(7630):560-564. doi:10.1038/nature20168 Additional Declarations No competing interests reported. Supplementary Files SupplyFigure1.tif Supplementary Figure 1: Cases of failed breast cancer organoid culture. A, B, and C represent breast cancer culture media from three different manufacturers. Supplyfigure2.tif Supplementary Figure 2: IHC score analysis was performed on various tissues and organoids as presented in Figure 2. Cite Share Download PDF Status: Published Journal Publication published 08 Jan, 2026 Read the published version in Cancer Cell International → Version 1 posted Editorial decision: Revision requested 20 Oct, 2025 Reviews received at journal 20 Oct, 2025 Reviews received at journal 15 Oct, 2025 Reviewers agreed at journal 14 Oct, 2025 Reviewers agreed at journal 14 Oct, 2025 Reviewers agreed at journal 26 Sep, 2025 Reviewers invited by journal 04 Aug, 2025 Editor assigned by journal 17 Jun, 2025 Submission checks completed at journal 17 Jun, 2025 First submitted to journal 16 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6906829","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":495819258,"identity":"d7eb7837-58c6-4756-8d6a-ada481e6623d","order_by":0,"name":"Chunyan Zhang","email":"","orcid":"","institution":"Department of General Surgery, Tianjin Fifth Central Hospital, Tianjin, PR China","correspondingAuthor":false,"prefix":"","firstName":"Chunyan","middleName":"","lastName":"Zhang","suffix":""},{"id":495819261,"identity":"96440913-98c7-4c9d-834b-49dc82e178a5","order_by":1,"name":"Bing Han","email":"","orcid":"","institution":"Department of General Surgery, Tianjin Fifth Central Hospital, Tianjin, PR China","correspondingAuthor":false,"prefix":"","firstName":"Bing","middleName":"","lastName":"Han","suffix":""},{"id":495819262,"identity":"cb043b10-c9bf-45f9-97a3-76e43d13eaa2","order_by":2,"name":"Zhihua Jia","email":"","orcid":"","institution":"Department of General Surgery, Tianjin Fifth Central Hospital, Tianjin, PR China","correspondingAuthor":false,"prefix":"","firstName":"Zhihua","middleName":"","lastName":"Jia","suffix":""},{"id":495819263,"identity":"7c17b61f-6cd4-4b75-8556-e8baac066dc0","order_by":3,"name":"Min Liu","email":"","orcid":"","institution":"Department of Pathology, Tianjin Fifth Central Hospital, Tianjin, PR China","correspondingAuthor":false,"prefix":"","firstName":"Min","middleName":"","lastName":"Liu","suffix":""},{"id":495819264,"identity":"c7d06bd4-0eb5-40b1-b5ea-df47dad79668","order_by":4,"name":"Yanxia Li","email":"","orcid":"","institution":"Tianjin Key Laboratory of Epigenetics for Organ Development of Premature Infants, Tianjin Fifth Central Hospital, Tianjin, PR China","correspondingAuthor":false,"prefix":"","firstName":"Yanxia","middleName":"","lastName":"Li","suffix":""},{"id":495819265,"identity":"d5de86f3-5bbb-47cd-a1b9-55eaa9253e2d","order_by":5,"name":"Jie Xu","email":"","orcid":"","institution":"Department of General Surgery, Tianjin Fifth Central Hospital, Tianjin, PR China","correspondingAuthor":false,"prefix":"","firstName":"Jie","middleName":"","lastName":"Xu","suffix":""},{"id":495819268,"identity":"ff627e74-8b75-4ef5-bc58-8c990f0e01ff","order_by":6,"name":"Jie Zheng","email":"","orcid":"","institution":"Department of Pathology, Tianjin Fifth Central Hospital, Tianjin, PR China","correspondingAuthor":false,"prefix":"","firstName":"Jie","middleName":"","lastName":"Zheng","suffix":""},{"id":495819273,"identity":"cd3e36ff-1d90-4a16-8310-4ed102b652b1","order_by":7,"name":"Yajing Sun","email":"","orcid":"","institution":"Department of Pathology, Tianjin Fifth Central Hospital, Tianjin, PR China","correspondingAuthor":false,"prefix":"","firstName":"Yajing","middleName":"","lastName":"Sun","suffix":""},{"id":495819274,"identity":"b851a43e-4d41-478a-a9a7-937424d35c3f","order_by":8,"name":"Yuting Le","email":"","orcid":"","institution":"Department of General Surgery, Tianjin Fifth Central Hospital, Tianjin, PR China","correspondingAuthor":false,"prefix":"","firstName":"Yuting","middleName":"","lastName":"Le","suffix":""},{"id":495819277,"identity":"e4d83012-8e3d-4d65-a0df-810221a9023c","order_by":9,"name":"Shupeng Zhang","email":"","orcid":"","institution":"Department of General Surgery, Tianjin Fifth Central Hospital, Tianjin, PR China","correspondingAuthor":false,"prefix":"","firstName":"Shupeng","middleName":"","lastName":"Zhang","suffix":""},{"id":495819278,"identity":"e2728b9a-1f15-4d4c-bfcd-d3c9030a9fcb","order_by":10,"name":"Zhijiang Shao","email":"","orcid":"","institution":"Department of General Surgery, Tianjin Fifth Central Hospital, Tianjin, PR China","correspondingAuthor":false,"prefix":"","firstName":"Zhijiang","middleName":"","lastName":"Shao","suffix":""},{"id":495819280,"identity":"08ef2160-2972-4839-b900-638c585dcbbb","order_by":11,"name":"Jian Wang","email":"","orcid":"","institution":"Department of General Surgery, Tianjin Fifth Central Hospital, Tianjin, PR China","correspondingAuthor":false,"prefix":"","firstName":"Jian","middleName":"","lastName":"Wang","suffix":""},{"id":495819281,"identity":"e7b4ca7f-0b10-4a77-bc78-a95d7b17797f","order_by":12,"name":"Xiaozhi Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAu0lEQVRIie3PoQ7CMBDG8WuaXE0ZtoSE8Qgje6FO1WyWVI4sqSLoCQJvge7M1OAFMEtIUIjJOcAiSA6H6C/53P3FAQTBH4oAxDjY5wJF5WkJvjerO55GstX0ZD5xPDuofElMlOnTiUPjIAcY7YmQSK+z/UUWDs6ebbsrIRGl94+1Khzbac4cJeFsU0pMDHKZEBNRcSad1ojkRLbI6s6vnETdkH6ZKnOHwfo4Pt6afrSE5IP/8T4IgiD45gVgTDaKA4zaCQAAAABJRU5ErkJggg==","orcid":"","institution":"Tianjin Key Laboratory of Epigenetics for Organ Development of Premature Infants, Tianjin Fifth Central Hospital, Tianjin, PR China","correspondingAuthor":true,"prefix":"","firstName":"Xiaozhi","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2025-06-16 15:08:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6906829/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6906829/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12935-025-04160-8","type":"published","date":"2026-01-08T15:58:01+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":88507138,"identity":"6d679511-cc3c-48b5-adf2-13d206f2dd96","added_by":"auto","created_at":"2025-08-07 07:36:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":2377298,"visible":true,"origin":"","legend":"\u003cp\u003eEstablishment of a culture system for breast cancer organoids of different molecular subtypes using commercial media. \u003cstrong\u003eA.\u003c/strong\u003eThe schematic diagram illustrates the construction of the breast cancer organoid system. \u003cstrong\u003eB. \u003c/strong\u003eMorphological and proliferative characterization of organoids derived from distinct molecular subtypes that were cultured in Manufacturer D medium at the primary culture stage, after passaging, and before and after cryopreservation.\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-6906829/v1/be9b6b48cb8a257a95b69b33.png"},{"id":88507208,"identity":"686c2548-2984-43f3-a633-f0952327d460","added_by":"auto","created_at":"2025-08-07 07:37:04","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":7727601,"visible":true,"origin":"","legend":"\u003cp\u003eCharacterization of cellular morphology and specific molecular markers (ER, PR, HER2, and Ki67) in breast cancer organoids of different molecular subtypes and the corresponding parental tumor tissues.\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-6906829/v1/f5910f7d7d561d105b5573b7.png"},{"id":88507210,"identity":"e010e69a-c0ea-439f-9fb2-3cae8a3f1680","added_by":"auto","created_at":"2025-08-07 07:37:04","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2659345,"visible":true,"origin":"","legend":"\u003cp\u003eThe role of FGF-free conditions combined with estradiol valerate in the establishment of breast cancer organoid systems. \u003cstrong\u003eA–B. \u003c/strong\u003eRepresentative bright-field microscopy images demonstrating FGF-dependent morphological changes in breast cancer organoids during dynamic culture (A). Quantitative analysis of organoid diameter and area distribution in FGF-treated vs. control groups (B). Data represent mean ± SEM. \u003cstrong\u003eC.\u003c/strong\u003e Breast cancer organoids generated in FGF-free medium supplemented with either ES or EV visualized by bright-field microscopy at passage 5. \u003cstrong\u003eD.\u003c/strong\u003e Histological validation of organoid architecture and molecular fidelity. H\u0026amp;E staining and immunohistochemical analysis of organoids cultured in FGF-free + ES/EV conditions compared with parental tumor tissues. Insets show magnified views of glandular structures (H\u0026amp;E) and biomarker expression patterns (IHC). \u003cstrong\u003eE.\u003c/strong\u003e Quantified IHC scoring of biomarker expression intensity in organoids vs. parental tissues.\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-6906829/v1/c2623c08d2707bde00909138.png"},{"id":88507261,"identity":"4a434a8f-48ae-4c2d-a0b8-02d259964823","added_by":"auto","created_at":"2025-08-07 07:37:15","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1958217,"visible":true,"origin":"","legend":"\u003cp\u003eEstablishment of a breast cancer organoid culture system using the FGF-free + EV medium. The growth status of the organoids was observed in EV at various concentrations\u003cstrong\u003e (A)\u003c/strong\u003e, and consistency analysis of cellular morphology and molecular characteristics was performed between the organoids and their corresponding parental tissues was performed (\u003cstrong\u003eA–B\u003c/strong\u003e).\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-6906829/v1/a3be78dad2712e9d01644c1f.png"},{"id":88507076,"identity":"c403740c-0d95-44d0-adab-1c476e46b695","added_by":"auto","created_at":"2025-08-07 07:36:32","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":2766071,"visible":true,"origin":"","legend":"\u003cp\u003eValidation of the FGF-free medium containing estradiol valerate in breast cancer organoid culture. \u003cstrong\u003eA–D.\u003c/strong\u003eTriple-negative, triple-positive, and Luminal A breast cancer samples were isolated, extracted, and cultured. The growth status of the organoids was observed, and consistency analysis of cellular morphology and molecular characteristics was performed between the cultured organoids and their corresponding parental tissues.\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-6906829/v1/399b3d8fa0254ec284cfa1ae.png"},{"id":88507128,"identity":"02879646-e7c5-4afa-ad8b-3e82d7807c1a","added_by":"auto","created_at":"2025-08-07 07:36:40","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":2151144,"visible":true,"origin":"","legend":"\u003cp\u003eThe relationship between drug sensitivity testing in breast cancer organoids of different molecular subtypes and real-world patient treatment efficacy. \u003cstrong\u003eA. \u003c/strong\u003eClinical data collection: pharmacotherapy records and pre/post-treatment lesion imaging (CT/color Doppler ultrasound) were obtained from breast cancer patients categorized by molecular subtypes. \u003cstrong\u003eB. \u003c/strong\u003eOrganoid drug treatment: FGF-free + estradiol valerate-cultured organoids were exposed to various concentrations of chemotherapeutics. Bright-field microscopy evaluated growth morphology at 48 h. \u003cstrong\u003eC.\u003c/strong\u003e Post-treatment cell viability was measured, and IC50 values were calculated via nonlinear regression.\u003c/p\u003e","description":"","filename":"image6.png","url":"https://assets-eu.researchsquare.com/files/rs-6906829/v1/14d29a4247be8e3fe7b891d4.png"},{"id":100069250,"identity":"2de8bcd8-2af8-4baf-8279-48ffcc5eb21b","added_by":"auto","created_at":"2026-01-12 16:12:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":18265812,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6906829/v1/b579cc65-b51b-4048-ac85-995f6773e814.pdf"},{"id":88507201,"identity":"53a02ab1-95d3-49a9-b04b-475529c24d83","added_by":"auto","created_at":"2025-08-07 07:37:02","extension":"tif","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":2386604,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Figure 1: \u003c/strong\u003eCases of failed breast cancer organoid culture. A, B, and C represent breast cancer culture media from three different manufacturers.\u003c/p\u003e","description":"","filename":"SupplyFigure1.tif","url":"https://assets-eu.researchsquare.com/files/rs-6906829/v1/e3312636ec246266127567db.tif"},{"id":88507182,"identity":"dd7b7261-32a0-4441-890b-3ca83de64bee","added_by":"auto","created_at":"2025-08-07 07:36:57","extension":"tif","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":755920,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Figure 2: \u003c/strong\u003eIHC score analysis was performed on various tissues and organoids as presented in Figure 2.\u003c/p\u003e","description":"","filename":"Supplyfigure2.tif","url":"https://assets-eu.researchsquare.com/files/rs-6906829/v1/f3b61feed709a53e19647cd6.tif"}],"financialInterests":"No competing interests reported.","formattedTitle":"Molecular Subtype-Specific Breast Cancer Organoids: Development of an FGF-Free Estradiol Valerate Culture System for Precision Drug Screening","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eBreast cancer is a malignant tumor with the highest incidence and mortality rates of cancer among women globally \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. The clinical management of breast cancer is challenging because of tumor heterogeneity \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Breast cancer is classified by the expression of molecular markers such as estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67 into several subtypes, including Luminal A, Luminal B, HER2-positive, and triple-negative breast cancer (TNBC). Each subtype exhibits distinct responses to chemotherapy, endocrine therapy, and targeted drugs \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. In recent years, advancements have been made in precision medicine for individualized treatment strategies on the basis molecular subtyping \u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e, driven by the use of preclinical models, such as cell lines and patient-derived xenograft models. However, these models do not accurately mimic the tumor microenvironment and retain molecular subtype characteristics of the parental tumor, leading to discrepancies between drug response predictions and clinical outcomes \u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn recent years, patient-derived tumor organoid (PDO) models have demonstrated immense potential and application value in cancer research and drug development. PDOs are three-dimensional cell structures cultivated from tumor cells isolated from patient tissue under specific conditions in vitro. PDOs highly recapitulate the growth environment of the original tumor within the human body, preserving phenotypic, genotypic, and heterogeneous features of the parental tissue. This unique feature makes PDOs an ideal tool for studying tumor biology, exploring drug action mechanisms, and assessing drug efficacy \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eMultiple studies have indicated marked differences in the drug responses among PDOs derived from different molecular subtypes of breast cancer. These differences include sensitivity to chemotherapeutic agents and the responses to therapeutic approaches such as endocrine therapy and targeted therapy \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. For instance, certain drugs are effective against Luminal A breast cancer PDOs but ineffective against TNBC PDOs, and vice versa, where some drugs demonstrate therapeutic effects on TNBC PDOs but are ineffective against Luminal A breast cancer PDOs. This variability in drug responses provides invaluable clues and evidence for formulating personalized treatment plans.\u003c/p\u003e\u003cp\u003eDespite the significant progress in breast cancer PDO research, the current PDO culture system faces two major limitations. First, most existing media rely on exogenous growth factors like fibroblast growth factor (FGF), which may lead to loss of subtype characteristics or phenotypic drift \u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. Second, the lack of standardized culture protocols for different molecular subtypes results in low establishment success rates and insufficient stability of PDOs from aggressive subtypes such as TNBC. These issues severely limit the translational application of PDOs in precision medicine \u003csup\u003e[\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eTo address these challenges, we developed an FGF-free estradiol valerate (EV) optimized culture system, aiming to overcome the barriers to maintaining molecular subtypes in traditional media. By systematically analyzing the growth requirements of PDOs from Luminal B, HER2-positive, and TNBC subtypes, we demonstrate for the first time that 20 \u0026micro;M EV can replace FGF to sustain organoid proliferation while preserving key molecular features such as ER/PR/HER2 expression profiles and Ki-67 index. Further integration of drug sensitivity testing across PDOs of multiple breast cancer subtypes with clinical efficacy data validation provides a high-fidelity experimental model for individualized breast cancer treatment decisions. This approach is poised to facilitate a paradigm shift from \u0026ldquo;empirical treatment\u0026rdquo; to \u0026ldquo;molecular subtype-driven therapy,\u0026rdquo; thereby enhancing patients\u0026rsquo; quality of life and initiating a new chapter in personalized treatment for breast cancer.\u003c/p\u003e"},{"header":"2 Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Ethics Statement and Patient Consent\u003c/h2\u003e\u003cp\u003eThe human breast cancer samples analyzed in this study were derived from patients with clinically distinct molecular subtypes. Detailed clinical information for each patient is provided in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The study protocol was reviewed and approved by the Institutional Review Board (IRB) of Tianjin Fifth Central Hospital (Approval No. WZX-EC-KY2024036) and complied with the Declaration of Helsinki principles. Patient samples were obtained after we obtained informed consent.\u003c/p\u003e\u003cp\u003eTable 1\u003c/p\u003e\u003cp\u003e\u003cimg 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++svMDM3h76+PoKDQ9Dfsx+mzpgJ9XZNYXcTsvPnEgmSkxKxbOmzGOrnxxo/JQV5aOnoIioqCja2NrzP6OsbYPv2bVj+4ovQUNdAeUUFCgsuo7q6GmPHjUdo6DkUFxZi7IRJiLwYgYSEBDi7OGPAAG/8+cd62NjYQl1DHedDQ6HadvjrGRiwsBEVGYVVX32Bl195DQmx0SguLkL+5QLIyMmhr4cHTgcFwcW1N/T19HD4yGFczsvByJGjkJObj9raasx+eB7s7Ox60uuOe+mAo7F+56038e777/Nh/eLzz3Gfzp8/j0mTJ+PP9b8xMdq9axfmzJ2H55e/hI0b/sKBfXsxdtw4tDQ1Iyg4GI/Mn4+KsjIEBwdj0pSpiAg/j+KiYiYRA7wH8p5He8njS57q0ViR8En70F9/rMfzy5fDzMwSP36/GlOnTYdH3344eOAA77ebN/6F9z76FCNGjGJlh6GhIQJPn2bS7ezsAgcHJ+zZswvWVtbcnr17d/PcI7Kpo63NhJbGOTsrHUNHjMGYceNRcPkyvln1BQvhreu5m0siwaWLF7F/3x4sXPgYgoOD4OTkjCOHD7HS5MWXX4Vr7z546/XX0NzYgHc//Bi/rf2Vif9zzy+Hrp4+Tp3wR2TkJURHx+DzlV/B0MgIKz/7mIWcsAvneU84cfw4kykZtPB+U1xcjIyMDF4vROyVlJWgo62LUWPGIjExAWtWf43XXnsDJmZmNxUmiDydP3sWW7dswuX8PHj7DMLcRxbgww/eh6GBAV585TXEREdh9TereO4mJSbiyOGDGDV6DK/Hr774HBMmTcbsOXOhrqaO9et+ZWGhsroKixY9jh3bt/BZcjH8AtzcPaCqqs7El/YzUzMzvPvGa3h4wUJ4DxiIC+fPIT09A1OnT+/WQhQREYF/Nv7F+4eDoyMef+JpbN70N5+/635bj8KiIqz6ciVjNW36DHz37ddwdXXF3EcexReffQIdbS08/9IrzCOCgwKRkZ7Oc+WnX9YhIT6Oz4KzwafRz6s//05nTF1tHROyfzZvhL29A6ZMm4GCy3k4eYKUIxOlmuN19Q3Y9PefuHQpgq2Os2Y9jN07tqKmoYEJ59JlzyE0NBRrVn+Dn3/9DY6OTqzE2LN7J1RUlOHk0hvFhQXQ1NKGtrY2Cy50mZia4deff+Q2EekjwkvCha6uPguHtr3s4NV/AMLDzjM3WPLk09z3u3mRIikhIY5xnTlzNtatW4u62lomtyFnzsLS0hwDvQdi7bq1fLZduhiB8+fD8dRTTyI9PY3XIs0RSytrnvuBAQGYMHEC0tPTERMdzXOflJFbtm7D2rXreO/umeB853svBaENxJEjhxATHcMLYcCA/jA2MUF0VDQmTpqE/t4+UkvSLOnU1WHbln/g5OzCGrLff1vH2kN7BwcEBgawJBMeHgZzUzM4Ortg25bNeHXFm4iJjmSJoLKiEosWP47k5CS8teIV7Np7EN+t/oalWCKNxkZGfEiQNDti5Gis+vIz2Frbwt3TC7t374SCvALUVFWYvEwYPwFnQ0OZHI2fNBnqampSIUxall9+/gELFz+BpIQEfPDe2/D06o8Zsx7Gqy89z7/TIgw4eRJjxo1jidPVtTeioyIRGHAKY8dPxJNPP8OTZMG8Oaj6nxbI2dWVN9Cff1iDMWPHM3mjReTZzwtGxiZ49rnnmexLcxGh/fD9t9Grlx2TepIuQy9cwLPPPMva1vKKclhb20BTXR1hFyNY2CT8c7KzUF5eDm9vb9TX1mDZ8leYVH/91Uq89vpbKCosZHL6w3ffIuLSJSxc9BgOHTyAvn37obioiKXqeY/MR2ZmBg7s2wcTU1Ne+KRBaKitxaOPLeYFQJqS6OgoPsCfXbqUF3xmZhZrFAoLC+Dh7sHtTk5JYfJoYmyCmJgoTJ06Hfv27+ONXFtLmwWGiPALsLC0wtxH5qOfp5eUC0qC4yeO4VL4BYSeCcaQYSOZKOkbGLA0nZGWwouYXEr69fNEVk42az1GjRqFrf/8w/0ldw7/4/4YOmQocvNy+XMyqZaVlcLM3AJJCfGoqq5i7aOckgoK8nJZuPnp558wcuRoNLc0M/EIDAzkw97a2po1jHQgyMnJMKmm8ZDIybM2Lj4+AcZGxqitrYGNrS1LzYlxMYCMHCytrOBg78Cakc2bNyI2No7buHPnduzbfwg6evpY+emH6N27N2LjE2Bmaobc7AzUNjRi+oxZePedt+HgYA8lRUXU1NZi+PCR+OKLL7B02TJUVVVi7+5dsLS0goGhIdJTU6GirIRXXn+LhYweXxIJ4uNimbQpKirD/9gx+A32hYGhEezt7fHZp5/Ab9hwWFvb4vfffsWqr1fj7NkQJCUlYZDvYGRmpiM7O5sPODMzcz4wSUtLJGzL/w7YJ596Brv37Gmdd+zG0AIbGxtoqKnjUmQkPv3iS5w9E4zf163FR59+jp/WrEZBYQEyMzMxZ94jUFdRxY4d22Dby56J8riJk3A5LxfFRYXIyMyClbUVxk+cwsS5Z7a5K0glJSfj1ZeW45vVa3gO/PXXH0hITGIN2Zw5c5nw1jc08BynNbTkqWcQGx3FWqWLERF8wJJFaN4jC/Drj2uQnpmJgQMH4sQxf7yy4k18u2olzC0teU6SJowwsbaxlbq9JLiSxrKqogwycgp4eM5cbPwfCZg+czZ6u/XB9m1bkJKcAjs7Wyxe8jS0NLV4rMaNm4DJkydg3tx5LHheuHAevezsmGCSNS8vLw/nQkNZUCDt45SpU7Fv3z7IopkJ7eix4/ieZ55cjBVvvI0BAwZ0P70kMogID0fw6QDMf/QxnlvkhkbtqauugqyCIr7+dg0OHzqI7Vs349ff/sS3q75kjdych+fg1MljsHNwQkZ6Gs6cOcMWSJpbb6x4Fa+ueANHjxyGr+8gXqfkHlNZVQkfH18UFhYy2R08xA+ZWZmsYCGFCJ05NdVV+PnH7zFp8lQW4G/mGkLjTAKxnq4+E4LMjAx2gVn11UomFBs3b8GZkGB8+snH+PjTz1loiI2J4mqeRMh27tqNhx56iIVhEhCWP7cUI0aNQmRkJO/Zf/y+loUz0hqfOHECtjbWvMcT/kRstv+zCYueepaFEprvb7z+Gtb/+TcrlG50kVD2+7pfeY21a6RpDqz+dhWvRRLySRnw5cqVMDAw5Lb9/NP3cHPrw4qjndu348L5UHzy+UpWtPyzaQPPiQ/efweH/U+yNYK0gKdPn4aykjLCLpyDuroGNDXUWYAvLa+AZz9PLFj4GEpLSvDJR+/jkfmPwr1v3273/+LiEry54iXMmTcfLr37oLSkGGu++Qp6hsawMLfAuAkT8def6xEedoHH+alnn0NJcRHefOM1LF32PI4fO4aSokKez0YmpjxfU9NSYWxsAkU5WdjYOXD7SdtMglFJaSmf/Y5OziwMktCy7tefMW/+QlhYmHc/v2/zjpLSMuzasQ0zZs3GhLGjWSAmIkqCPll3rC3MEBB0muccCZmk4KH9X1ZOFgGnTrBF5sCB/TzXLczNoaWtywoALS1NREVGw2eQL2JiYrB6zQ9S86fb7NJNvy4VoSVSQxsqacbGjp+AUyeOsYli4qQpuBgRhqXPvwhVVSKD3QeykIS07pcfERwUBPJinDX7YSanGakpPFktLS2Z+FmYm6H/wEHYt3cPystKMWzESDZb2Ts4wXfwECZQH3/0PspKS1FQcJk3WnIFqK+vxfQZs5GTk8XE8J03XoNbnz6IS0hERNh5eA/0Zc0aDdwbb76Nrf9s5kPdwtJSqvYTmqQp/vKLT/lgJVNP37592cRLkltNdTV693FHi0SCE0ePYODgwUhNTmFpjRZQSOApTJs1GzNnz0FcbDRWfvYJho0chVPHj7GWZce2fyAvrwhXN3dkZqTx4uk/0Bfz5j8KNTb1d3+RCe69t97A5ct5bP7Q0dVDXEwMvvpmNXZs24K4mGjeZA4f2IfcvDwmPM6uvRFx/iySU9IwcfJUnAkO4vuJgJJ0nZ+Xy30bPXY8flizGo0N9WxevHTpItzd3ZGelobKyiq0NNazkJOZnY3w8HBMnDgJDQ11sLKy4e8S4Xv/3beRnZXFpH/58pfYfYO+P3LUaCQnJaGhrgZmJBVCgsjwMCxavBi7d+7EqtXf44P330ViXCwLAPakCT9xDN7eA9l1wMjYSJopyIftyVMnEH0xjDfxsROn8uFPhPZi2AUU5OeyMFVTW8dSdVxcLGtJ6BCzsrSC14ABvAGQpmDOw/Owdu3PPDcnTJyM+Lg4btsJ/yOoq6+HiaEBZBQUWYvw8Sef4ZtVK+E72I8JGm2UQ4YO53mUEBeNl15dgdjoGG7HmdOBrDE4fPQIfHwHMdEmcxYRYTs7ezYJXTgXwoSD+tNQVwtfX1/WppIbQh/3vtixbSt27N7H479q5adwcXZBeVU1DPT0kJgQi5T0TCjKy/P6I414XnYWhg4fyQfz5s2boKmlBQd7e/gfPoSpM2eziXzTpg0oLSvDF19+zWu1xxcR2tgYHNy/lwnStKmT8ej8+cjKyUFVZQUMDY2gpKKK5MQEJCYmYuaMGVBQUkFqagrGj5+IrOxMFhyioiJZO0T7B/lfkhb325Wf4qFHFrA2s5edA2tKSIvi1sed105AwCmsePMd3pB/+v47PohoTOmdZMZd/uJLiI6NZavDmDFjYWhkjGP+R6CkqAAPj744cfIkdHX1WOtH5PtWLyKM5HZAGJLv5oXz55Gfl8OkiTSylyLCERIczGZtJWVlPL7kaSaR27dsRmNzM1tZiKgqKsgh4FQA5BTk8PBDDyMyKgoNDU1IS0lCv/79+dAa6OOLp59Z2mbe7b7F5PkTfDoQx/2PwsXNHX/9vhbeAweioKAQb7zzHuTl5LH2lx95j/P29mEFBAl3P/+4BsNHjMSzTy/BoscWsxCtpqqGI0ePMKmhA9BvyBCs++03JrlysnJ4dNFiJkZlRYVITkuDqakJpkydju07duDZpc/D2dmp+wYDTCrI5SCHzMZNzRg8eBATVtKurf9tLVa8/hYLLX/+vhZr/9iIjz94l+fOa6+uQGlpMSAjy4Jqbl4Ovvv+JzZhv/3m63j66WeZ5B48sI+1aVOmTOG5O2bCRNRU1yIiIowtl2QtIOGJrG9EOGk/ovm5+PEnYWtn3y2h3bZlC/T0dNmaQ3NAQ0OThQFS0JDyhrSxLzy/lAUT0vStXvUlRo8ew8Ktjr4BCzKk1SX3iW+/XsVn9N49u/Da62/im1Vf8jolt6h1a3/BitffRGpqKuzseiE/Lx/BgSex4PEnMXTocLZ0jh87Cv7HA2BlZX3D85AUMaS9p4uEEBLIFOTkERBwkgUwEsSWv/QKPv7wfRQVFeHd9z9EcVEB1qxejRkzZ8DM0oYJ/2srXoeOrj727t7JFo8Xlj2LvQcPsysfub01NtShoroWWZmZrDSbPmMmdu7YDhk5eQwZ4seklDTly55ZgvmPLsK48RO6JbS0d7254lW2HJIVkVyHIi+Gw8PLm9ugqKCIDz94B9raurznbNuxhxUny59fig8/+gSHDx+Enb0DThw9BEhk+ZwgskfKnCFDhkJFTZUFDfI3Jy3yV1+uxLDhw1kZQPOR9g8am2HDR7AS425fpaVl2EmEduYszJoxBfPmPQplFWUmubT/hpwOYIGQBC+yLJL2/6GHHkZfr/44cfwYFj32BAtc5G6RkZYGzwHeyMrIgJm5GWuyiU/t2rkN3373A+wdHLvF/273txtCK0FpcRHq2P9GGalJCXByc2etloWVDTPyyIgweA8azARXmov9U5KTWLvk6tYHppY2rP04dyYYPr6+7MRcVFDA7zMyMUGLRBanjvvDZ9Bg1mSqqqlBW5fcHOiS4OC+XWxGGew3lH2QyEWBzJBVFRV8kKckxMPMwhKp6elorKuBhqYWJLJyLJH7DhqCnMx0GJqYsIQt7UWEODk+FonxcRjgOwR6BoYoKSrA0aNHMHXaDCbgVZWVjJ2BsQn7PcVFRzFOsZERMDY1Z+kuPiqq4+bqAAAgAElEQVSSNcm2Ds7Izkxnv6kNf//FJkU7RyfMnfsITxby4bKwtJbab4/8ZuOjo5CSnMR9d3TpjbioS7y5yikoIiQogAlzZXkZm2rd3NzYv482xkGDh0BH3xDnz4WwxpPwooDA9LRk1grRIibBQNLcCENjU1RUlEFdXZMJna6+PptFR40dB0VFJV5IEydORnV1Jft36hsY8nvycnMRcPI4xo6bwD5VCXGxKCspZC0dPScrKwt2js6siSXiQ3MiOycbS597Aa++/CKUFBSw5OlneAERKSdC4t63Xw+CgsACUVVlOWtzyOxIRJEECZpj5LuloqrGvrQaWlqszacFTdoHcpUhnzPyRcvNzoS9ozNi2OwkYT/O5IQYaGrpsDmctAyamlooKS9HRXk5vAYM5HlOtacJ04bGBt4Q0tNSERsbg6HDhqPocj6TmLLSEphb2uDUyeNseiTtKc0VIhykySbmTs+kdtAGn5uTDU+vATxu5PNLPlrpaSnw8OwPeQVFZKQkQU1dg320yacOzU2oa2xGckI89PR0YGlly5s1EVoi9DSnL+fmsHUgISEepuaWbAI+fHA/a/uItN+qeYk0kSQgUf/ycrNYW0TCUFJSIsaOn4Tc7CxkpqeygEsaDdJwkAZdT18ftTW1TEiDggLYPWPG7Ifh6+PLpDYzLRmW1rbsUkDaatKoaWhqsvBBGm0SIEiDQnI3jffBfXtZS0FaNRIojE1MeT6SXyBpDZ3dPFhTo66qAlMzCyQlJ/E8YH/bnkUtXbW1UF9o/6O5Q+2gfUtDUxvJCXG8BqiB5PtIwZy095ozuZAgKuoSLkaEswaMCD/5P9NY5GRlQVtbC+Fh4YiPi0H5//aeF158hYlpv35esLWzk3rvoPakpyQzZgZGJricm81KA/J/JOzo4CZ3JB09PSZedJEaY/PGDSgqLMAgH1/oGxmxFjksLIzXNhHOsePHY/jIUYi5dIn3cHqOiZk5crIyWNhPTUnm+UTnSlh4BB6aM68HMRoUs1CPs9Tf/gN4jJSUVWFsaobCy+Sm1OoPTvPK1b0vxxZQzISjkwub50lLfu7cGdja2MDIpNVtafu2reyqMmz4SPbRNjU3Yw1ebU01NLR0WKCn9UfuBuVlJSxgXIoIY7/lphYZnAs9hxeWvwQd0nTeJGCJyOGZkBCsXrWSzbyLHnuchYexEyZyew8cPIAPP/4Uzy19Gs+/8CIOHjyIL7/8Ci+9tBwOdr3w94ZN8OjrjpdfeZ1J9WOL5uOjjz5hy2Z0bBzkZWRYGURCxCsvv4i33nkPaamkXbdHVmYGTgecQH2zBB593NHbvQ9b335b/zf7Hd9YOyBht4pPP/4AxcWF6OvRD80tEsyYNYsVW999+w2eW/4ifvz+OxQWFOLFV15hSwj5E/sO8sMvv/wEK2trfPzJ5+w+RTE1g4YMwZFDh1h5QIF35CZBGvrjx48hLS0VFPFBWsbt27eguUUGeTk5cHVzw4KFi7Bpw98s2Dq7uHS/J0kkiI6MYqGGuMhzLyzHgX27ceSoP6+xxYsXsyBM84982seMGcPC8VdffsECDbWPLIJ0hg4YOIiVPSQckRKABGJSglC8Dp0VdN/6339jzTv9pHPl88+/ZHe1hY89DgsLC2kpxy3fR5Yr2scNjU0QceEcjIxNoaahidOBARjo68tz5tyZM0zmTc0tcPDAXjjY2TNHKSwklwMLlBQVsUvY3t07MPJ/wlVpUSHk5BWYtzm6uiHkdBCfxeSecKtnwi13sMsXu81y0BoZ08Efr//enqZZ6ZqeRprD4aosNm0NumEqmfZmdkmF07X1HZGd7duytLB2SunCX21rnLSRIl3T9LS1gyS7fXv2MAEcMWoMS0ztgYdSqh6vDJS0bemuyz3tW2coO7eh8xzpwfjTwU4LiQ5/0rQFBZ6CkZExu0hcdfUoyrVVGJL6lO9u/ndMNynn240wb5+P3Y1JTz/vvHZ6+t2btfWWn3WdFEo9eBa5vhCxJkvJXLJcSOkq1Mq+Og1mt2vkBsD1eK517VyX/nc3vzoi2NujqK+/H58OPIWzwcEYMXoM3Nz7dgoc795ydlULr4lOb/u0czuu2vMlKC0rZSsCk4q2i4S0Y0ePwNLCEiNHj2XN0DVrtsseTuSc/NZJIOt2eK5u9LXr+ar9vVPaSSlSdJFfe1lpMazYVaPL1c16Ki0pZaWGqbm5VAFWNFC5OTms1SYSRP71mtpaLJiS3zhZGcgFi36StpDaRi4B5MNOCgmKR9DU0uQAql9/+oEFaydnZ3ZfsLa2YmUCCXQ5uTns2kDknwOUGxtYcCILJ5FIcrWqKK/AbHIZ6XaOS1iwJOutjW0vlJeVsQKJAspoXZKvf2lpKQs25CedkZHOCjC6Jz09FdraOuwuRNaWA/v3sAWBLVeJiWyh0tTQZGJJSh4ih3SRTzy1jy5yTWsNtFZkzfKYcRNY6JfqksiwEKmspMTKABorwp4u+hspM+QV5LkfhIOamjpC24IEvQb4sGaXArvIP/Wv9b/z/kOuSWQNIYVBezAxYUpuZ2SNIFcVukjxQG6KU2fM6oHAJlWvbnxTO4frnDWvu8V1g6yBN3xJTzngbXbpRl/vntDepReLx14PgdaDjpy5SePU/aby/wNFPpfa8bjmMPr/gYHoZWcEyABJEeZt6YukcHX6f4Ffe7q9tlRa/2qfr7su28dJ+r2MMwfci/ZfA5Y0eXVveKzeQo7rrgyjK6OQjoEUFhWy9UCHNaw9u3JzyYVOGVpalKVAGiHoem1qb/eN2n8tU6KAT9KSU5ulT73X2jci92Q9aO2vNG1ux6Q7dnd1O8kljdzl9PUNO0ClDB3kckduBBSEKk3aTcrKQM/S0tLq2eCIu6VCQBBaqWASNwkEBAICAYGAQEAgIBAQCNyvCAhCe7+OjGiXQEAgIBAQCAgEBAICAYGAVAgIQisVTOImgYBAQCAgEBAICAQEAgKB+xUBQWjv15ER7RIICAQEAgIBgYBAQCAgEJAKAUFopYJJ3CQQEAgIBAQCAgGBgEBAIHC/IiAI7f06MqJddxUBKtrQflFkLUVX09X6167RshTxzOknuNhD69Vax737TBRXKtJ3vf36terbMl20Z6ZrjeeXohpf56js6z/5Sn+vNLs1LdzV6cY6/ntV6p7bifq+q0MpHi4QEAgIBB4gBNrOk44Wt0hxjrTdfFVKPcry0nyl39KcR5QZho8vOmBukBXiZs/hzDKd3tkd6tLef1WWlM4ZKLp7wdWfC0LbM7zE3f8BBKjcJFUIoyToVPmI6nBT1ShaqFRZjcoyU4lkyiFIBSIogTQll6e8kgEnj8HSygb1dbVc2pASVVORBKKdlIPxqksi4VrflAScEvxTvkaqAkU5IVXV1eHauzfk5RQ68izW1tVy1RmqKJOclMhtcHR24ko5Dk7OTKWp+piiwrVFTFJSUriYANU6p2IJVMudCkPIyshx9R6qZEdFK6h8NBXYyM7M4DyRVCFOV0eX8zDm5mRBQ0MLiYnxnAaHEvJT3+g7hAHlilTX0JB+8/0PzBXRBYGAQEAgcCcRoFzCVAWOqgQa6BtAT1+PC1NR3uHurpKSIi4CRedSfn4el7ElNQydZVSmnPbvK9fVhLW6poZLspMihgot6OvpX5MmjZ5D6cmoSqWMDJWzuPqiYhxm5p1L9t48nZy091PBEkq/pqyixvl/qR10ZpIqpyfp2ASh7W4Gic//cwhQfe0/fl8HV2dnqKqpQk1dE/Hx8XB0cMTadb/ixZdeRlVlFfLyctDHox9XQqFE3lRZ7s8/fueqMJTUfOSoMVwelSo2UXJuO3tHyMl2IrUSGaz79SdOgl5QUIBetr1w6tgRjJ0wGScDTuHxJU+iqKCQySIlcKeKYVS6luqSU6ldIthUh52qtVFpWiLR+/fvw6RJUyAn13mzkWDLls3Q09GBkZEhjhzcj+q6eni4u3M1JwMjY/j7+8PPz4+r1FhZ2zD5pj7rGRhgxszZSE5K4HrvHh79cPTIIc6VOHvOPE4oTuV+KT9lYOApzHpobs8k9P/c7BEdEggIBAQCt4iARMIlqU8HBbICIjMzEwsXLkRDYxNXoZOVk+cqllR1i4pfUEVFKkahpKTMVsQzwYGorKqGR9++XDiDyqJHR0VBRUUZCnJyXJk0MvIiNDW04OjkxFUY6aKiG/v37uLy0PQ8KpNM1b3MTM24eEVRcTHy8/K4Omd8QhyMjU24OiPdQ4oQqmLn4OCIr1d9yeWenVxcuZgGFVOhcs9UpIOqoxJRLricz8qU3m7ueO/dtzBhwkRW0pSXl3MxDqpYSeWy62pruCSzmroaF9KgSnKFRcVcndHI2JjLL/O56uAIDXV1qQAXhFYqmMRN/yUEikuI0K6F94D+LO3SJuJ/9AhrTs3MzLk+N1VdcnByQv/+3sjLz0NsdDT6efVn0kklhWkz0dTSxoSJk/HrLz9xTfFnly7rVM+aq0Fw+ceYmBiu2DN61Gj8+tMaWNn04jKrI0aOwm/r1sKjbz949ffmxNwbN/yJ3m59mASnJCVxmUqJrCy8vb0REnIG+/fvxeLFSzB+4kQmme1V6jZt3ICW5kaYmZki6OQJNMvIwsfHh0vv0iZD5SE1NdRRWFiI+QsX80ZHNcWpDaRxPn70MFcYoo0s9Gwwl1g1MjHHH+t/4zKUCxYswIljR/H4U0tbJeZuKwn9l2aM6ItAQCAgELgDCEgkXOr4wP69UFVRZQ3phPHjcTEyEvLycqwsOXXyBHr3dmPLXU11NRSVVdhiRhrdmqpKrg5H1ctoH6ZS2VRi3czUFC1NjVBW08ChQwegrKSMx554srWAQwtARSBWfv4pXnz5NSgoKoCqkgaePM6Kmbz8fKiqqvB9RBzTs7JQWV4ODQ116OnpcVU0Ku9LJdsT4hNga2vNBSaobDz9jaybVFqaCHcf975cTpkIrLKqGoKDT8Pc3Bxubm5obGhAaGgoyivK+VzS09VBWmoanJ2dYG5phfzcXDQ2NaO0rIxJNCmRSBNtYmbKpY2pilt3V/eEViLDDWXFcpuv4dXVPNrU2nf8gOvke8i9kLIKSEepXinv7w6hO/V5u18K+7C0VSHpiS/KnWrHdZ9zxUe0tV5mq29oR0XOzj6mHe4trYSN50aHz42UmLf78bSP6x2fOzcHq7CoCNu3bsGshx5m00pSUiJSkhO5pO6Z4GDMmb8A1ZUV2LV9G+bNXwhyBTh39gyGjRjF8OzfuxtaGhpITU/njYW0qCTd+g0d1qE5JXJM+Pz0w3dwcHTG4CF+KCkqxNdffIw5Cx5jkjtuwkQu3eh/5BDs7O3g4OjCBLhvP094enpi+5bN0NTWRlx0FEwtrDBqzFis+nIlXn1tBUvs1BZyB6CBIkLr1seNCfn6X35AVX0Dnnx6GZfLpPKZO7Zvw9Tp07lm/ORpM5GYmAhf30GwtrHljebgvj3wGz4COdlZrC2g/k6aMg07tv3Dm5SjoyO2bNyAp5Y9j+amRh7znlb1ubtTmPygW99wTeXWf3l+9bSfV/lz02B2VEBr60wnH+eOvbi9o7yHXCnjfH3/5562qIf3t+9pV5UVvuIH19qmVh/0++q63v7V+W/tjb2Zv+F91SHRmLuCwPU4hTT+qtdrjESCs2fOIC83B8NHjmK3soiw84iKjoZX/wGIi45EcEgI+nn2g6KiMmxteyElJZmVF6TVVFVRZosdkVqy7FVV12DeI/ORmZGOorwc2Dn3RmlpCcgFjfZv2v/poj3+s4/ew9QZM2FgaIKiokKEXQhFxIXzGDVmHHT0dOHu4YmTJ/yRlJgAczMLDB0+AgHHj0KeSKWpGXbt2sWkctLkSTgdGABNTW34jRiJfzZvhIWZGU4GBMHCzATGpmYY0N+blSFKyioYNnwY4uNiUVBYiILLRSgpKYSXlxc8PPoiOTkJ9r3suHS2/+HDmDR1OmTl5bF3z27ExcXCrU8fWFtZY+q0GZBXUOg2lqRbQkvm1Pi4ONjZO6C2uhopqUnQ1TWArJwsKsrKmPR4D/SBorR1lKWacRIkJiYwyVBRUYGllTWMjE24JCzViG5sbOI6ztSG1nrOCqitqYWcvDwTEVKh6xsa8UFP99/riySt1JQUWFpbISYqik0K5B/i7tGX61Xf66u2ro59NnvZ2bMEmJqSDCpHKCOR4ZKz5GuTnZMNWRlZKCopwc3dAyrKKrwoo6OjoKOrCycnZ/axpPFobGrifpHGsaamBkqKSmhuaUF9XR3/PTMjjf2F6P7GxgYYGpm0nckSNl3QUXg3campqcX27VvZnEMbxdBhI1jIsLd3ZALn5tYHji6uHcNCphXChDS3jfV1PDfJVBIeHobZD8/lOUomFkUlZZ6z+bk5GDDQF7JycjhxzJ/nr42tLcpLS3H00H5MmDINpwMD2axCWtEOeU0CHD/mz6YWAwN9BAUGwGfQEGz66w/eXOwdnVBSVMybT0pyMkLPhrBbAJEFIuLkK6unr4/gUyeQX1SEvNxcboO1pSVU1dThM2gwSoqLcOzIYZbKiflNnzETtr3sERsdySTbrbcbdu/ZhSF+w+Dp6cV+WTTm5EO88e8/8cyy5xF+4XzrmmT/rfvjysrKQkJ8PKhCMpm0dPX0kJAQDxNjY/Y/VrgP1tk1SEkkqK6qQkhwEGtiSAvj5uGB+JgYmFlYICI8HKampjAzt8Dl/HzeY2mTd3B0RHZWFtTU1eHo5IyggJMwMTFDeXkZKsrL0X+gj9QmutsdPfJ3Cz17BgqKiujn2Z/Nhnl5eYiLjYGmhgZMzC0QExUJQ0MjbjcLevfBRSZYMqMmxMXB0MiQ/ebpwDwbcprPEgsrKxTk57PZlfC3d3C4D1p9pQmVlVWsyaJ9guZ2WVkZ6G+052rraLMfIgk/+np69027ac+8fPkyNDU1oKamxu0qKirms0FHRxvkW1pVVQ09Xd374tym9pF2sqDgMscm6BA5lEhYu0nzgkre1tXVsqmdNJ10nnV7SSS8d9O+SooQOi8z01KRlZ0Na2sbRESEIysjHb3s7aFO7mL6BoiNjeHYClJokNR+6uRxdm+TV5CHXS97BAUFQEVZCc6OTtAzNEZZeRmKiorQz9MLgSeOwczSCq69+yAm6hI2bfwbBgat893J2RU/fr8ar7/5Dk6eOIakxHi21lFsSFxMDCtCBvkNRXZmJpPcIX5DQdbN3r1d0djYiLi4OD4X6X5a1yVFRdDR00dgwCk4OTlhyNChiIuNg6trbybl9E9dTQ3VNbWws7eHmZkZCi5fhrGREWMqJy+HsAsXkJ+fj9593NndoKaqCgO8fVBVU4Oqygp4+/je1DrYLaH9bvU36NPHHZWVFdzJhvo6yCkocufiY2OZPD625KnrBqp0O7g3vEGCbVv/YdW0m5s7+3uQXwb59dEkSCXSkJ/PE6qyqoqdlEtLSvhz8veLjIriA418Utw9+vFiuVcXEf64mGj22Xx5xZsc4BNxIZQ1gxMmT2Uzw72+iktKsPWfzRg/YSIK8nJw9OhhKCqr8kSihVJRUYmw8Avo188LpwNPYtLkqXBy6c3SnEQii5ysDHh6DWBfFzJd02ZK5noaDzLRkxm7vr6ByaChiSlio6Nw+XI+XFzJD6ccNr16cf1xMjOQAKWiogYnFxce97t1NTU3o6G+gYksHcb0frpIGUMHgQwxoxtd1NamJhawWn2UrtT9Li8vZYGL/KP4eR2ZE1of1lHpnN/TfE3972srnYPJMmliW1vU6iRP/khEYEzNzK9ym293oae2Ef6kZ5eTlWVhr71H1D56NwkeCgryLKjQGMdER8KtjzuTYDlZuTYMWr9FZLG5uZG1zZUVZUzeSZC8H67q6hrs3rkNZhaWvA+Rxp02bWrjhdCzmDx1Otdal9rK8y92ioL8Dh7Yz8LVoMF+fCju270Dw4aPwM8//8zzaOr0mTgfeg61tTVw6+OBkuJC+B89CrtevVjjsv63tUziTU3N2ERIZsP+3j43n8N3pI8S5OZkIyQkGGWlJRg3YRIfbkcPH8TePXswZeo0FlDPhYSwQDfzoTlSmQ3vSNO6eQgFQRJ5bWqhwM1ITJ4yDfr6Bnj91ZdYKCRtmba2Lk4eOwrfIX7sq3i/XGXl5SzAksAzctRIePT1xPnz51gLlpudzZo/ErqJPC57fjkrJu713Kd9LfDUCURHx8DGxgajx4xDXl4uDh/cDwVFZfYJvRgRhqqaWkyaOJmJ+r2/JAgKPMUCo6m5BWbMeohjD4iwUdvpfCTXLDLPk8KBhPx261BP296+7xO5J20qEcT2PZ/M+UQgSeCii84tOnfY6iGh/9fznk3fac/W03pSSJCdlc6Bzjo6enwvnQl0CJHgc+rEMf6sv/dAPvgoEItM/HQDnQ10HktkZJGWnMh+t7r6Bnxfax8laGpuYrcIOgeojU1NzaiqLMfFiIu8Xsi1gQ1ObfdTH+jcJOLaHkDdcR6yMUrCfadnUZAc/aT9gwK3s7MzWSHWy44Eyxtbgm9MaNtU6u+89RZeXbECe/bsQnpKCtSUlaCqqYXpM2fjz/W/Y+78+dDT07/DPnUSbN2yGSEhIWzqdHF2RlTkRfYrlJWV407W1TWwxoJ+J/Cpj0TGHp43H/v37YWKsjKUlRRhaWEJT59BnZI09XSq3c79EpY6v/3mKyQnxmPpcy+ylo/Mu14DvGFpaXXPNxrqXWlZOX7+4TvWZpWVFLHkLyuvyAemlpYmNHV0sXXLVnbeNjM1wfARoxEfHwd3dw/WwNJGRFpO8in94L232d+zqKAAufn5GDtuAk4eP8bki7Sybu7uHPlPvkKkNUxPTYWhgT5LvOQK0NhQz2YSVzd3PpRvnoDqdsamp9/tHG1547QipPm5bsaDjtf1LGrzRq2k99BOcTPefd3v3sRURhsSbSrXI/N1dfWsEWgl/nemDz0dgRvdTwf3kUMHMXnadGzftpUPmIfnPYLkpCQmXKNGj+nQCN2pd97J54SFhXEWijFjx3HwBpkdFeTlsGfffjg5ObKFjA4sWiPkA7dtyybum56eLgvGpI2hCGby9+4/YABOHT+KsROm/CvCMs0ZMhuSP96Mh+ZAQ10D0ZEXcbmwAGlpaZCXk+OMGuYWlpg4ZRq0NCkKW0rXpDsJcpdnEXEgInD+/HnWkg8a4sftWr7saXh69eeAFiLnx44expxHHuXz5H65KJhz/7490NPRRr/+3qzkIe1sQlwsYmOjWatHSh8yFS9cvOQGqQj/zd5IUFlRjm9WfQEnB0foGhrDb9gIpCQl4M/166CnbwgTE1Mm5K5ubvAd5Mdn/T2fJxIZHNy3u5UoNjdh0NARvD9u/HM9W0rmP7qQhU7yU502bTordW6V0N610eCt+tr9mlYgWd3IZe7qAONrW0J+rbIy0rmYEaEmTTwpSu7kRcSZCP41mYS6vOTmhBbAZx9/AB8fX+RkZSI5NQ3jJ0xilbibex/s3rUbzy1/6S4EiUiwadMG2NvbsxkrKvIStm7eAHMzU548cvKKHMhDs4c6SpHYJHHLSoAnn36WCS35iKipKKG3szPGz3j4DhNuaYdKgurqKo4wp3RP06bPgpGhIUvPtKCVlaUwUUj7qtu4j4gkCRAPz5mHovxcNkto6xli4uSp3EY6UCk6cdz4CXjj1Zcwb8FCxMXFs/ngmP9RPP7kU7C3s4OCohI++uBd9O3bD6kpSRyNOXnqDA4mkpeTQUxcIigJgKmJKQcv0QStJzNUfh4TMxVVDWSkJcPQwAADBvqgr5f3vSe07f6MHTtVV51rO/CdAqU6SF+nz24kUnX1K7zGH7HTwHbOIXjVztn53V1Sh12jI77yPNqkr/KD7Xj+febr2M3cJg3tH7//in5eXtDVNYT/0UOcfSLy0iUsfmIJDPT1O6J9b2OZ3LWvngs9h6yMDF5v5GoTfSmMNS0bN27Cu+99gO+++xbpaWnsHz1lyjRcuhSOktIyzpxxOScTo8dOwKWoKDi7uEBRVoZdEQbz4XvXmtz6YIkEl/Py8eXnH2HYyLEYNHgwGhob2eWGLCCHDh7ks8HLqz+7gnl5D2Tycj/40hKhJT890nI+seQptgZR1PWXK7/AjBnTmcSQL3lMTDQeXbT4Hp0f1x8/8p8MOHEcAwf5Iuz8BcyZ9wjk5BXw6ccfYO68R3Ax7DzPo7SkJPiNGAVntz73uP0SJq8b//odk6fMwKWL4Rg/eRqbrKOiItmSYmRowGkN+byJicIgv+F32I3xFtaCRAZ7d21nck0KGWoT8Y3dO7fD0cEJEeEXMHCwHyvOyEJMQcPdEa4etaJzrMmN/Lg7nzXS+qh3+Oh3Eiy7nlk39RvvFHPTow51ZZ/tOXHv3Hlzc5cDiYTzpe3buxsjR41m0+fRo0d543R0cOAJRymB7kbEM/lmUsohcwsL9gsLDAhAZmYGpk2fzukimppbQylILZ2RkYHc3Byoq6qwb0iLhFISxfHfZkyfwYfbPb0kMrygyWxBOUnJZ5VSYNxzCbQNFNKyEt4urm6oLC9l83JGVhZHxBPG5PtG/i7kt0PpnUhD5+DohMOHDuLC+VD286P5QebvFa++BGVlVUyfMZ3dDAKDgjB65EhkZKQjPT0dvd16Q1FBiaMu6SJTBpEq+r+zS2/s3r2DTQzDh4+AFvks3bOAHnKBaMDxE8dYk56Vmc4bLrlDnD0Twu3q7eaGc2fPMvkgEyUFWJFvVElRAVJT05CZlckZDMikHxEexj7TJBiQRYE0EhXlZejj0Ze/T9o38ksmDQvlhSX/2s4XEYSzZ4I5LyxtnKdOHOf1SLh5DRjI64R8/8htgA7nixcvwtqa/FyNWeiwsrHmaNPsrGyYm1twrkHyGVZQoojXGjbV09iSb5uZueV9MzelW7cS9nPbtXM7+7z19fBgH+HsnBw2cc+YNQs62q0uIPfjRal06MCkOAU6EAvy81gMiYqKhsoNfXEAACAASURBVB/5ocXFoqiwkOfMnr37MGyYHxN00nZGRV1ibSIdtJGRl9jiMW/+AvbHvev7i0TCPnAb/v6LzwJfHx/UNTRwrmL/I4c5g4aRkQlrzXv16oVBQ4aw+8v9cJGrx4a//mBXG1prri4ujD+tldTUVBbeKXqc1hJbIO+jiwJ+Th73h22vXqipreO2kzIhMiIMA3wGsaaTNLTkLz9lemsQ0F2fCzfFpzU24tcf1sDewZ79xd37erJvaHZ2DgwMDXlfpPaSvz9lZenXfyBrBe/pJZFB8OkABJwK4CwCw0eNRnFhAac7JEUV7a0UDEwWErKMUNzEnWuyBNFRlxAUFMSxChSnpKunj5bmZnYfo590JlAqR/K7JXcZ8pfW1NZhTkQXpZBsDzilM4ZcCOiis4ysqe1ucfQ3OuvpPCd3Qfq77+AhnI5LIpFpjVcilzcJBZc1sqtBWnISLG1sO1yIiI/Re8mCR+4MXKyImUILt5PcH+gnuVi2u+vVVFcyduQqxs+/A4PdrQ9tt2L+XSMcXSoT3ZKps72S0703cXWYae/7LAydp1UXU0V7CDXD2aap5HFp1xBKcOK4PzujU9DbtVcPTNV3bV5JuWrafHqfeHwRjA0NMWbcBHb8J19GCupTVVPDuPETmThdCD2HqdNnwMLCkv3yyL+V/Aop4I3SelECbCIf4RHh7G9E5IN8HS3MLeDtO5gd68nR38d3MC/4tP8dWEOHj+xkMpawz9bBA3vR1NiEseMnclYDZxdX5GSlczDB8FFjcCYkGJfz8phQBJ8OgrWNDW+6f//1J+bMmYuq6krItIBNkY1NjfAbOpzdTcisSgKKra0Ndm7fhqeeWdqWVPt+WDdSjlenSP8r32ifm+3zVdpn3YP7rusK0tb+nqpaO9bnv9CPjrZJsbbv9ZruCsc1Z0on6wu39cauRf8Csjd8BflBUv5PimbvZe/I5vD2aoe09mn/SUmMh4KSMpydKbj1fljHEo6nuJyXDVNLa847Su6DaWkprYn+jYyRkZrCqakcnV2hpqp6LyHueDcV4UlKTGQtrbq6Bvuxk5sNuQg5O7uwJZhcnsgvuD3Q7Y40XCLBn+t/4zFm8qmtzT9LSsrg4GDH409xRBbm5gg9fx4O9vacR3zcxEmIjYmBiooqPL28EB0VyWS3proK6ZmZrCxqrK+Bk4sbetnZdTSVgvHOh57Fzh3bsfCxxzlOgsgrBU2nZ2RwtgWaZzl5+Ux0Dx3Ygz7u/TB69BgOSCRlIwlatKRcXd34/Cdhl95xzP8IY0OujK4uvVnRSMGA9na2OHcmBPpGpujbrx8rWnq61V2zpFuam+6H2X5H5oB4yL1HgBa7jKzMHZG27mlvOPCrGQvmPcyaTjI70obsf/Qw+vXz5EhNcsUhLS4lpaZsBGRKPel/BLb2jsjIzICqqioHbxgbG2Pk//w4v1z5OZ5+ZhlSU5ORFB/XGs3p7g4ymW/d8g/GjRuP8RMnY9eObez+QZG1bJ6VSLB/7x4cOXKIN1U/v6G4eDECMrJyKMjLxbIXXuS0KocO7mPJnSq8ZGVlsHTu3scdFPRXWFCAQYOHoL62ll10KGsFZUXQ0dXHX3+uZ7/BJ55Ygj9++xVPLX2OK4zdHwfhPZ0F4uUCgfsTgXYyfo2Q0JFssU2Hcr8d71eX6L5KZmgLHrofXFKuHvQb6Q7votAjkWDDX3+i6HI+azApyD0jPQ0xsXFQUVJgv2lTc0sUFOQjOjqaA0H1tLXhNdCHv0dEfMlTT+OfjRtYi0oBZRmZmUy+B/v6wGewH6xtel1RRpH7UH4+B6+/8OIr2Lt7O2x7OSA26hJCzoTw+8gKk5yajhHDhiE9PQVlZeWYOWs2W8Io4Ivy61Ixh/r6OtbykjvPxImTEHDqJCtxKGicCCwFml+KjMTUKVNZmWNr78SWxrHjJ9x2coHuNbT353IWrRII3F0EJBLU1dTgg/ffw+yHHsK+vbtgYWmNyopKzg1LJprJkydj6+ZNWLBwMQeQ0BUceJIDeMjlgPy6yTRlZ2eH1LQ0DqB78uml8D9ygN0yIi9d5I1n2XPLEXruDPp69udcg9u2bMakSZNRWVUJe3sHloC/X/0NfAYPYfcbCjCUyMljwaOPYd+eXexXTkR4754dLFUrKCihrr4BpSVFnOEjKyOTU9xROzPSU9k0HRMdzZqcL776mtMuWVrbwEBPD59/9gnefPtd1p4IQnt3p5h4ukBAICAQuC4CEgnW/vITTE3NmeiFhZ2H/+GD7LYYHnoOnl6e7F6Qnp7JmlBNTXUY6evBzMaOs4qQO9q8BY9iz86dnEqyl70DFBXkudgBWpo4t7iSigprYPV09Vn4yc7KxC8//4gVb7yNcyHB8BzgjV9+/IG10hQwTgQ4KTkRORTkaWWF+rp6LqNOZyGVdG9uqMeCRYtBMQFknczKysaSJU8gLiYW+ZcL4Nl/ABchIhdFismiPOhRlyLg1teTNbazHpoDpdtMsyoIrVhPAoEbIEA+QZGRkewzTqnXyDRGppcTJ06wX10/T08OarCzs+fSg6RJPRN8mhc4majIF2/EiOGorq3nQgWkgSVTEJlnyH2BiCT52FKO5XZbS3hYKGqqqtmv7NCBfVj6wsucEik9NYVNcZQXmHycySfKwcEBlOyANMeUFolyBVLwED3z9OnTHFRJ2SQOHzrAlVocnVyQmJDIeSpTk5PYpErBd+3vpqIK5EM475EF/0LKJzHtBAICAYGAQOBGCJAJn6x8pCy5nH8Zp0/5t+Zsl5VHVUUZstJS0Nd7EGefUVRQRGzURRgYGnN6Kxk5OXYjy87O5gqR5Gsdfi4Y6ppa7G7AuWZjY6CtowPbXnYcE0IKl+TkZM4hSz77Onp6HJBPVkAjEzNO3UrBnUbGpqD0lHTm5eTkogUykJWV4cwsqioqkFNQ4PPFysYOLq4urJAhRQ359dPzyf2B4qBc3PogMS6WlT4OTi7sIteePvNWZ4UgtLeKnPje/xMEbuLHeI1PMTh9EvmxGpuaXj9Kt1PVJwaws7+jRIL42BjoGxhysQYy05CLQUcyvxuWwmpLoAsKJIjkvL5cFrfr1fXd/P6ORIGcZJ4C8QwMDP6fjK3opkBAICAQuF8R6OzD3RpYR4SPLIDkWkYKF/q9/aL/sy81BcxfJ80Wl9GlnOttgZmkkaVzojWAlK5O72vz6afjiYLJKBCNLkp1R+4L9LfWPLlUobEZEpkr2XXo/RzScAOHWAoKo6s9b27H8++Aj70gtPfrXBbtekAR6BLM+C/34kZJxaRpBn/3Vks6SvMCcY9AQCAgEBAI3CEErheIKX0g4+2cFVc6cKNgUCmCRO8QCp0fIwjtXQBVPFIgIBAQCAgEBAICAYGAQODfQ0AQ2n8Pa/EmgYBAQCAgEBAICAQEAgKBu4CAILR3AVTxyPsHAfJDJTM6+x21JZeWV1C8qlpRq+sO1ajuWmWrtR9UypauVmPOtaYUqjp0Q2f2tny2lEqL/JqoDRSB2l6nuwMpiaTj720vvQpESmZN/kqUtLrVV6qrj9JNTE2dcx+3uRSQHxM9hxL0U++oYAP93qmjnfx729wo2j/sUkWm1XR1b0xM989MEy0RCAgEBALdIdA5BditplTrvNd23felcTnomobseu3o7jk93e+lvf9qv+H2E7g7VNs/F4RWWqTEfQ8QAhJOG3LymD8UFOSgrKICE1NzXLoUAQ01dWhq68LByYnrzDc3t6CoIJ/TmWRlZnClL1MzC86rRxWbqIpQcUkp993CwoLLqfr4DuogfkQKqXoMVerR0KAArk6XRIKoSxeRmZ4KDU0trsR24dwZNDY3QVVNHf0H+HChBSpykJKUCG0tba60RMnGHR2duMJYclIirKxtkJuTzRXGqBoZJfW2sbGFUnvgV0sLR5EqKCi2OeJf2aCoOktaciIn5SbHfsplSIFmKckJ/Hx7ByeutFdTVQEZOQV49vdGYkIcV3Nxc/fgRNxVVVXcx+aWZqSmpsDe0QkmxqbM7SkAoLDgMkhIoPRhItXXA7RMRFMFAgKBfxEBCadMpEI7VMbazt6eA6OkvtqKfZSVl/LeTSWuq6uqOa2Wjm5rYBdlFKB0kVT8gK9rAq0kKC0r5ewFMv8r7UtFkChQjK9OPJeyHMjLK0BDs+1M6+RwW1lRwcoQquTaEbB8k07w/S0t0Ogc4HyD+6sqKjj4TUtbB1mZmdDX14eiktIN+nLtQwShlXo2iRsfHAQkKCktwWeffMw5VakcYXJyEg4dPIBnlj6PfXt2o2/ffnBwdEBNbS3ioyPh3LsPp9GKi4mCobEx0tMz0FBXyzkA9+zZy6TTxcUFllY2XMKWokzPhARhoO8Q5OVkobS4GHaOzpy+pOOSyOCnH9fAycmZyzxaWVriTOBJzH10MTb8/TeeWbqMK+Rczsvh0sBOzq7YvWsH6urqOR8fpeui/WjEqFFMVs+EnEZ9fSOXvPQd7IeqynLEREXDy3sg8vNyERR4CjNmPXyV9pnKLO/c/DfsnFygo2eAHdu3wq2PO28S7u4eqK6sQnBIEAYM8MbHH37AJRwhkeGSik6OThjkNxThYRdQW1PDpRQLiopAucJGjxuPnMx0TjmWlpaOkpJi9B8w8Or+PzgTRrRUICAQEAjcPQTaCmE8+fgiLntPKbKefnYZ75eUO1xFVYUrQ5KVkCyKpaWlTCipIiWVBCbSSSm8GhqbuPIWnQtUKEdWQmVrC1hh0djYhLq6GlRUVMDAwJCtea1KhisX5SfftX0L0tLTkZmZiUceWQCvAd5copaUONQuKihEpasNjY3Qx92DLYdaWtqorqpCdW0tp4fMzEjHsBEjuQpZeVkpf1dbRxdVlRVMqOm9VCyBFCrxcXGcTnLk6LHQ1tbm/tBF9xDZJUUNWS4ppWV9XQ3Kyyugqq6Bzz75EC+/+hqUFJU5jaSauga382aXILR3bwqLJ98zBCQsqX74wbt4dP58Xih1jU2c1JlqYpMgOnLUGJZqjx89BBMTMzg4u7Cku3vnNgwc6IOggAAUl5XB3s4BqqoqyMzI4PKzllbW6N/fGxERYdj6zyY88eRT8OrvjdOBp/inOpX87UivJYOffliDwqJCqCgrc637TRv+hOcAX05yPW7CZC4JeO7cGU590rdff6xf9wtXT3Hv26+1RreBMWysLWFra4fK8jIEnQ5k4mthZYVzIadx9swZPL30ec5Je+LYEUyYPP0qQkvkeOvGP7lQgpyCPLJy8uDi4oqy0mIul0h5CfcfOAA9HW2UFBVgzMRpMDDQx+nAABgaGsGltxuOHNwPIxMqT+iJpIR4hASfhpOLK3Zu3QzX3r3hN3wk/I8e5fK/ml211PdsDogXCwQEAgKB+wSBNkL70Qfv4vU33sbZsyEIu3ABebk5UKQSxU6OoDzgRFxJK5manoXamiq21AWdDoJHHzfMmD0XgQEnceHCeVRUVkFLTRVDhw1DTl4e4uJiUVJSCje3PigrK0VBQSGTzs+++BL6lIaR0zPKsNVx146teGjuAi6RToV2YqOjODcsWf82bNjAFSQV5BU4vy3lPDezsEJfD3ccOXwQsnIKUFJS4gJDVKDhqWeXYtuWLXw2Dho0iEuuG5tbwb6XDYICTsLE3IrLvpNmuqS4EB99+jn27N6Ns2dC4O3tjeioS6xtppLulJd28OBBOBsSgpS0DCQlxeOxxU8gMCCQifqixx6HjW2vq863rqMrBaG9Udm3zo+6VV+Qm3LtLh9K+47ufD/u1QRv9yG5Ez40d6MP12vfzd7TNemHtONDz5TGh+d2+kiEthRvvbkCc+c8AmUVZZZed+/eieHDRyImOhLTZs6GiYkpAk4dh56eAZycnblEX3ZmBsaNn4i01GQoKqlg+/atePnVFTh53B/qaupc3UtP3wDWtrY4dvQwpk6fCVNTMwQHBcJn0CAuR0u5+qhWOWRk8MOab1m76u09kKt2ffHpBxg9bhKKi4owdvwk6Onr4cL5UJZQqWjDP5v+hpm5FZeutba2hZGREdLTUuA7yI9rbZMLAuUO9Pb1RX5uHleQmT7zYTYxnTpxDGMnTEJdbS1LzJTLluq+b9mwHlraulBRU0d4RDgTWipzSBXM9AwMEBwcDBMTY6SlpMJv6DCEhp6FiqoaRo4cze4aVODBwNAIiooKkMjIstsEEdrEuBjY9rLnajEH9+/DlOkzWJNL2gE5uR6Y0m5nqDu+2+rny3kS5RVuce+4Iw3p4UOk3V+lKb95t/fk63XtevvZzdraQ3ju2u3d+ep19/lda9htPvh67aZH9mR/vs0mdPv1653R9+u5faPOdD0vu8G3jdC++vKLWLhoES5djEBNVRXvrxYWlqyVJaJKuWLJHcHM0ordAoqLi+HWpw9XAdMzNMZx/8PIyc2D90BfoKkeKSmt5xRV35JXUEJqSgrSM9IwatRonD4dhIfmzOX9mJ5PRLS0pBhbN2+Et89grhRJCpWI8POorKzCUL+hXAnM3NKGCwGR5pc0s3R2xcZGo6y0lK2Thw4dxNhx44Emik+R4WqXlVVVHIORk52D8opKaKirwtTMFMoq6jh+7CjGjBmHixFhbBkNCw9nZY2NtTV62fX6P/a+Azyq69p6jXqXUEG9CwFCBdQpEr33Yhswxi224zg9fi//Sy8vTvIStzhx4t5Nx/ReRRFFqFdQ7733gv6sPTNCkkURCCScufmSADNz77n7nnvOLmuvBVdnZ5iZj0J2Vjb0DfSQn5sj8vFRUadFvIGKY/p6etjwxJMi8W5oaCBQvQFXo+7rXTd/EgqFyKrR6ybWgulobujUtreytsGVmEuiMuHnH/A1F+W2c/o2X6DKEr13puHHjBkLDy9v1S96aVXLS6qaWKo/UoGCOEh7B6cb3x8Cwt57uZ9uKMQRcXZxRn1dPS5fughff384O7sMud3uZpxt7e2iNuXm5i4vFLErVdXVaG1uhJa2FpydXVFYXIT21lYYGZtiytSpQq5Mpyzq1Ek4ODnJRNcj+bJaY1wG0uv5qO60s6MD+fm5MDQwlEnJpi1Ryurj5xKcyd/e/SLMzOQH778DbW1dmJgYiwoJ7236zFlIjI+Hmbm5OJDNLbzffMmAEmPb1taKoKAQRJ0+ibTUVMyZN18WnKsZ6RIdbtu6BdOnzxAnrq6mGqOsLFFSXILqqkqMHe8jtuOiwVINX/ZTp47DzdUDbu7uUpo5fvQgFi5ZjvPnzsl8GDNmHGprq+U9o2Z39LmzyMrOQWhoqCioxFy6jPDJk+Hh4SGqZIyiE+JiMcHXV+APDfV1sLC0lEia2NfFS1dIZF5dWSkRL6ERVy5Fi43ppMbFxcLaxgbnzp6Djq4OIiMipVmN79jp0yfR2tyMpOQkmJiYYsmSJSKJG3P5kjjRxOlGR1+Av7+fZLpZiiJ0oaS4GJlX0zExMBgfffAeHl27TiQb7+X5DWoeKxQoLi6WjDUxv6Pt7CVQiLl0CeMm+MLPz28ALNmgrnB/vqxQSInu3JkzaG1rhYW5OQyMjFFWWorgkDCkpaZIdoXzj5AOlhAvRp/HpKBg1NTUwEBfX9SALkSfh5uHBwpVVQTO2R682v0Zuep9VYCYtxMnjsPAQB+R02dKsyOhO9k5ObKR2tnZIi0lBePG+0g2f1CYwfs0dq4qNdXVsuZRVa+srEz+HDApUDJkhYWFiLl0UTDq8+bNx9WrGdDR1oaH15h7VjIaklti82r39Z5noFxqlQIp/L/ODgZ1urK2skdAj4HokFz4bk8iHazK9aCbpe0uWXNkLnSz5VYB7gtcj2Sccn/3tv7f7Ui/9jv1ftZ7PAotSUCw/C327uTYde/Axko5W9qBTcqLFi/Fjm1bxKl0cXWDtpaWlOmZMMnOykJ1dRUm+PrByNgY5uYW8l5RhdLRyQkVFRVSvg8ODhY1MPZgEPc6wX8i2trbMNZ7rMDsQsPCpVrJa7IXg70R589GiWJXWWkZli5fgYryMumTiIycgU8//kCgDTa2drLmp6Ykw97BQX675YvP4BcwEeYWlhg3fhy6uzpFfpc+AM8ROWOW7JM8F9cBZm2dnVzEP2DChfuEtZU1rly5jIrKKoHw8d+tLC1hbGqKkqIi8SuKi4qQl5crPsiqNY/i4vlzsi8vX7lahINo9CkR0weEH9w8Q6vqhn7jjdfgM348ujo7EBNzBa4uLoI75AZL/ENKWiqef+EllbrQ3TsgfSeSAps2fSFSapQXpVPCxho6qzNmz0N5eRlSEuNkwSwvLYFPwCTkXEuHjYMTDPUNkJqaChMjQ3Ey5i5aKpm1B7a5DvAmpaWl4a//9wpe+dOr+PjD92Tjov2mz56rdAKH+aiqqsKO7dtES7mhtgqfffoxTM0sMHfeAomG2DTEksaMmbPwxacfY/HSZQgNn4ptW74UCVgqjrCBiOUONg1dTUuTiW9gZIjos1EIDA4VZ66irAx2ji4oKy1GRnqqyK6y+58lfz4fRmGJCXHQ0tKB/6RJ92ybzi6lmoqwHFDJRKEQPK1anEstZELMkJLgQIl/5Xe6rivZCJQLVbdIzBLH09HRKdlH5cKrdLx5DZ6An7Okw0WOGU1eSSWaolKXVQimiGNR/kY5Hl6/srJcnBB9QyNZdHgN5WKpup5qs+JtyHiF8UC1UXR3SzTNpjRmg7u6OuU76ihWPQblhqfcCPk5F2VG1cKYQKYDbi68b164W7no8hKlpWW4di1dnCyBLmhr35DGVSiQdfWqKMWYm5sjISEeU6dFSjb3QR10tL/8/FNpVqPDz2ZABmJsBGRWe978hfD19RvWNeBmtuBCvWvnThSXFEugFHUmChN8Jsg7snffftjb2eHF735fyn3MvBP20VBXh127d8HPdwKeevZ5/OG3v4KFpbUkGvgOubq5IiRs8h1ssPf4hBRaohN/7OgRGOjpYfa8+RI4ZWdm4tSpkyK5yfne0twiDu+KVY8IVvDrjSr3OI5B/pwb/N/fegMFBYX429//iU1ffIa4KzH4zf++Ig2T586cwonjx+U9fPmn/4O3Xv+r7IFLVz0ijaTDebR3dOJi9DnYOzhKMoll3DOnT2PugkXijB8/cgiHDx/G088+iwvR0SLdHRgYiI1PPX3/58NNDEMH9vQpBj0GmOAbAJbd2QfwxManZT7EXL4sjt2SpUsRPmUajh4hDMxRkiTDO1cUqKquwuGDB+Dr5y+ZUrLBxMZewaljh/Hcd74nDiqbYufNX4DpM+fIenmrg3uSOMMKhazx3E9kz9FSYmfVSSDZHygqq6WsdPETYk3V31Xva1yLuV5zr+J51Ww+3BuUil0KkaHlOk+YmnKd5/rfpQwuurpw/MhBuHt6wWeCn+w3vcfD73FcVZXliLkQjfmLl8laz/Gqx8rvyLU5Fhk3xLHV1VbA3Wus6t7UMZdCrq38Ps+huHHfSmUfJRuR6l6Z0CQcgR/x/NnXMqQB2cXVdUAz39ah/eXPf4b/9/NfYM+ur5CWkiQ4PnevMXBwcEZKcoKkm3/2i18LTnHonEYFtv97gsfExEgp2MvTQ7KaLi5u4mAxgq6oKBeHhzdpNsoSNlaWEmUvX7kGJ0+eRFdHu0SmYWFTMGbsuCEc2+CWMzr/mz/7BEmJ8fjBy/+Nf7z1FsJCQ+XBL1mxGoYGqg7DwZ12SL9dV1+Pt958HYaGRmhsqIMWHTGFNuzsHDDKchRcnF2wd+8ekUU1NdTHslWPSPRPidS6unpcOH8Gk6dMg629A/7npy/Dy9NTFleel539sTGXBY/DiJLd/ow+DQ30ROI1Py8fdrY24IvOAKmpuVkA7nRA6PDeDgQ+pIYYgpPxZVT6uoPJidxwTO/+HeqtUPag1cqU99ojgaiOGIbAnndyCmYrjhw8gKUrV2Hf3t2SvFq2YqVk4U6fOoH5CxdhtI3NnZxqWL4TFxcn2QziurlRxMdeQX1tDa7ExcFJsjHlsvExY//jl38q2G3qsHuP8YKhkYl8Xt/QIFnz4JBQnDp+BIuWLJcs3f0+ON0rKspw9PBBgdCwcsfmkWNHD0nzIRlDrly+KNmZhUuWSbPjcB+cnvl5efj8s0/w81/+Bo0N9Th+7ChmzZ4rm+m/3n5L7oNOwYaNT6GqohwFebkICAq55yD7nu5dMvqN+OLTjxA2eao4IVu+/FyC2NWPPob2tjaBOK1dvwHX0tMROWs2jh0+JOt2xPQZw5NdVihQX1+Hzz7+EG5ubpi7YLHs02fPnMHMWbME7rV185cybzlP3D3H4NixI1iwcDGmRUQMr0OrUEj17qMPP8CMmbMRERkpjlZGWhoSrlzElMgZ+PzTT4ThZtacuZgUGHxbh/Zrz783pWKfDwegueqj4thvjVfvNwNUo2VPUiiJFW8cyvPzP3QYdXS4VtyQQe8TSKivy/PQkR2AOUFZKO9dPadjyyTSwEwLynHcKgHa+/5vwFFuRxF5a4cWwN9ef1UaVGqqKpGWng53N3fJBunr6cPByQVxcVcErOvgwLLx0GVot27dLNFwwMRA1NfXYuf27VI69vf3Vz4AFYaCjhWxJsSDdHd14Nnnvo2jR4+guKQExsYmmDVzBkKJNxkm2AGxJSeOHUVyYhzmL1yM01FRCA4OQXZWJlateQxmpib3tMYNxY9ZvuTizs752spyKWEqtHUFJ8mGKB6FhQXwHuMtWFHiNK9duyYNQOfPn5WyxtSp06QL8Xe/+RUmTZqE8rIS1NU3SnaWWEu+E+nXMuFgR3ylLhwdHCTSY3atpalRIkM9QyOkpqZIVmrW7DnwD5g0jA6t6iUa+L3qI3t9A1rRy6kb4MEwYmb2lFlfltgYjCkdX+VFJBtLJ+Rmc7X3otXbYe7nQLLMyAzlQIeai5cRuzL7q844qRa4ARe/G9nooZhvQ30Olrj27tklWavqmhpkZmQIDCom5hLmzp0P/4kTYaimfhnqiw/B+a5cuSJVDmK3r53HPwAAIABJREFUDx86KNUQwgbISPHDH/wI77/3LmprazDa1haBwWEoLshFXUMDWltaUVFagsCQEOTlFcDJyVFKk0ZGBpgyLfIBODDKbuz33nlbxjZ/wULJ/nD+nj19CouWLceli9E4evAAlq9+BCEhoSMCcsD3jdR3H7z3Ln75m98J7OPo4UOYMWu2lDkzUlNk4758IRr/84tfSSk3PzcLk0LCh9ehZWXlejcyUpOkkejYsaNSEfLzC0DkzFlSdWFi4tvfeQknjh2RbOeB/Xvx5FPPfJ1ScAjm7Z2egmtOYkICamuqMCVihjiubICaO3+hQJa4P7LngUmrb7/4Xem+JyVVSGjosO3b6nvjdGaDLJ1WYYBRHTEXzgnV46mTJ5SwACMjBIWEQ/t2Kdo7NZp8rxf/962SBD37wu2cRPXF+znLaqe6t8c70B7U36G+nb93Wxn1ocdN36YpTCEd1xcuRAuYlxhaOhx0Xq2srJGckgJXVxcEB4dCT29oswGkOWJGj1lCTnbieJmJWbR4sZTcWMqil8RMJ3GLJSUlMDMxRsCkSWhoaERmZqaAmBcuXizUEsN50MHIvMZuQVd5ka/ExMhLwOyzlMKH+eBzJbUGcW4tzY3IyEhHRUWVdP3zYNcjs7HEkKYSX2lqBmfiPc+fRUJ8PJydnTF5ylQps7/84x8IqH3WrNlSziD8g5hLbgrERXt7e0ug0dbaAi0dHSlT07ljYOLs6o6oUydgoG+AqRERN3juHrB9mptbUFhUKED7XTu2IzgkROhTkpOS0dhYj4kTA5GSkoyCwgJETIsQ7B0j99zsbNiMtsGlS5eQnJQEdzc3uHt5CQbV23scRltboqKyEl5jxqKyvBze48dL+V7NIctAkTCZcT4Tvr6QKxS4dCFanNDA4BCcOnFcNmI2fU2ZGiEYLOLSKsvLBHN16dJlgXUETgoUTNbZs1HSSMAsODN648ePR+a1a5g5Z65ci1Qr+voG6OhoQ21NrWSo+lCQPeBnMJjLca0vLSFtWZRk2IhNrqutQ0lJsWT7Z8+eI/NspB5cu/hcPLy8sG3LFplj5KhksDN1agRSU1J6HFo+14AAfylFchPNycqC97hxaG5uFuo34uIWLV4ES0vrIUww3MxyCsH5fbVzhzRvBAcFo72zU95/4sidnF0E85uQmAg/f3+EhU1WZY2HKvFx90+U1EZcu0h91N7ehtycHMEmZpIP2tJSAnfb0baYMXuOvGf1tbVSgRpuDDD3kmsZqQJx4prd0FAvz37hosVi2x07dsDSwkLuhWtWfFwcnnnu+WF2DBWSdGL1jxnZt99+SzLGXDvpmMfFXkZSQqL0NTy67nFxbIlfZuJnuBJR6pnFAI2YU/YfODs5obqmGmPHjpe+BI8x3ti6eZNUIpnQmTw1YvAZ2ptOYQUSExMkaOF1Z86aLb0P/Q/2hVy+fEn2Kjc3D2jfphmXyUA2PDNrTx9OfZSXl2PP7l2Cf+X855rJOTTQ0dXZKX0aDk7ON23O6vmdKkEy0HnY/1FZUSGVhh4c4N2/0soQ4JZNYUr9JNmsJfJQaMmfqYrExZZOJUtkQxqUqG5IySHMNLly8WNkqsZp9L9nUV/iWPh9lYPIv6u/PxLK1jfao27Yc3Bl6Xt80rf5OZ+zgNz5v8RSqv7Ln7H0Jvx4qs+5yDD44uIqeEviW4gB0lIIx2tE5HSlM6rCh9IxUj4jYoKUWKG+pXlVmV71nJXnG0zJfmhtU11dg6NHDiM+Ngbjxo3F7HkLJROdlJAAX5/xmBQYCBNzS8mgEUhP/DA7My9fjMaKNY8Jzx4dTgYCbORKSU7GExs3IvPqVcl6s4GJ3aOh4ZOljLx/7x4pd1pZWyP67BlxbIghu1HxUAgZ9+6d22TxfPpbL2Dzpi+wbPlKaYRi1nfNY4/jelcnLpw/i4BJQTi4fy98/QPkeYzx8hInmvfArlkC9pkF54bBJgI6yTu3bxMcGJ2kqxlpcHF1h5kZsecPy6HogzHrPX85/4ZvNt3efurZz/dLvc7xHeF/e2O++dLJ+st3SHpnbqjG8Sp8vwQXLWTtD8Zp5FWYGVSuEzcw6Or1hA7BDRz7SHoKClm7lMuMcodQrmlKfHr/vU19P7d/mvf/G2QSoa21dfWk6ZP9Lcr9uEuql3Q2XD08ewJVId0fpgql2hpMmnAMbNguLyuFnr4+bG3txQmnQ86MOR0brj9sNOT9MTAfCYcaV8q5wQYwwiv5bwxueF+NjY2SfBtSiI9CgU8+fF8y1WSo6WhvkypTXkER5s2djezsHAm+Jk6ciNNRpzFp4iScPH4Max9/QiiyaMcpU6YgLz8f9vYOKCspRlx8vDi+bPbmfjDGe2yPeZlQSklJwqYvv8QPfvQTVFeWS+8EHV8G1Gw+4/txKSYWHm5u2L9vl/RKsD+B1fFrVzNwLfOa2MbPz1/swWCXjeZHDh2U5um8nFzMmzcPKampKC0rg+8EH6QlJUHX0AjTIqYPSR/WbR3akTChNGN4iCwg3VXKpqKH9SCfH5tGzpw6iVf+/Behqjp0cB/s7exhamoCrzHjBCPM7mfSdvFemV0tzM/FxKBQwW6eizqFGXPmSjmttLQU1tZWCAkNQ2FeDmLjE8Aol0wGsXHxUmZmJeGppyi48IkwJLDq0duhJcbv3Flyw9rKQhQdfR5NTc3QVlzH9374E4y2tcfl6HOySQeFhEnJkd2zxJAyeztvwWK8869/YOXK1cIly2YHYtGZKSHV1Tvv/AuhIaF46Xs/QHZOtohKMBM8klyQh3U+acatscCQWqA/7rIPXl/1xkpmTHXVkbAW92G/UVuj9x6hKoOrM3oPGId/6+fTC37GL/aMUcntKsdQszIoFPji00+go6OAnp6BVPFY3a2pb5Q+FhMzc+E858iKioqF8URfVweBYeHYunmz7FMbntiIzz/+UCoL3dc7UVxcKhXCaVOnYGrkDKGF7NljFMqkyScffogf/eRlbP3yM9jYKQWGyIwzftw4ycYWFhYjOGgScvNyRQDhqaefRUFBvqiPnT97Vqrh9g72sLSyRnxsLFauXoWd27YJlI6qm6ymMxBnD8DqVaulv8bW0RlWVlZYvGTZPVf6NQ7tkK40mpN9EyxQVcVmouMiosBMK/GYjIZNTU0x2tYBOlpATW0txo0bB1//ibKYcTFgZnNqxAwhqmbn69TI6Thz+iSKi0ugra3AshVrRImMETQJtVnyWbZyNc5GnRYcMjn2du/cjvE+EyRDm1+QL1RHLCt9+P67skioO0SZ1SAXIDtUfXz9JdvLLDGzHxODQiQzS5gLG/28x3qjo/O6UMc9/8J3JBKvramRDnV2IJMOhVy4bMwgbCQ9LQXGRsZCBaVxaL8JM1pzDxoLaCzwUFlA5dA2NzVi2cpVqKysEp5xOoOZGWmYMWuOQACZGc24elX6WdycHODo5oUTJ49LwuSxteuxf+9u2ZvsbO3RLQw/CliPssCkoBDhwCXzBLOpTL9SXv2Tjz/CD3/0Mi5fPI/AkDCp9GWx98XRUei3SHmpr6cDGxtboRjjHsmqHx1aJkaWrlgliRf2i9DRXb9unXDlUuiBimTsB/D08JQ+gcmTJ6MgNwce3uNkP+Jv77VpVOPQPlSzXDPYB2EBctiSRouytOSYJaaRvKxFRYVoaGhCSEiwYB7p4BKjyWWCxNRJiXFCfdLe3oHu7i6hlSNOlZlc0tR4jfGWZkA27pB6jmosxEq2trZB30BfMrvXMtLEIS0rKZES0lPfel5wzfl5uXD38JJsMR1Rlpe9vLzkutVVFXDz8BRYCOntiJnNzc2V8VJphqUwwh54LeKdKapABhB+Z5SFhWRwyVbCrDMxuaXFxdJg9SCptx7Ec9VcQ2MBjQU0FngoLKBQCOTNwsJSEgvkKb944bxwxBJWxL2DJX3CNCi7TspGsklwrScsjRlb0kDq6hsIJIUwMzbbcc+ysbEWuAcb+plRJcUmD2JaqV42dVqENKkywXLpwnlxNvlnUgxSYt3R2QW1tXUwMTISDlzinZsa6gRnTNo+fUNDYbLgtQhrI062qbkJ9vaOiI+LFVhPZ2c73FzdpdmcyRlyuBMGIVSU93BoHNp7MJ7mp99gC6g7NNUk2kI5qyTSJlZbjn5UJdKo2N0lXK03DiVWTzCRKgxy7+bP3vhuRrxUeyE/YWNdHXT09CWCVtKr3MCT88/KyytLdr0/4xja21phYGikHCv5CNXjFsoV4h3VlC3CAtgH2kCsFs9KKqAHhcP8Bs8iza1pLKCxgMYCd2WB/hzmN3holQIadAzJUkMctZq/VfYKFfsW/7+niVHFOSuc7Cr+12sZ6TAxNenhgReCEulzUWHKVdzk5N6lQ6zsgyHFl47w8aqb8m/0Aik7hYh/7s3/LuRg6jER56/6O78nexO52dXc7ndlqV677e2awu7x/Jqfayzwn2WB21KV3MIcfTzdXli4wVrwXscgXvLDi4EerLk039dYQGMBjQX+4yxwC+7ah9UWmgztw/rkNOPWWEBjAY0FNBbQWEBjAY0FNBYQC2gcWs1E0FhAYwGNBTQW0FhAYwGNBTQWeKgtoHFoH+rHpxn8HVugv7LWQKooPbjZ3tQ3vf98Q796QJqWgUr9fa7bS1qQA7+ZGkv/m1KTZBL/OlhatP73pL5u/3LTQH/vTYqtgSDc8VTTfFFjAY0FNBYYEgv0UpK8LQxsMBCCm8HSbneOe4Wz3ed9ROPQDsms05xkJFuAnftUj9PW6oaurj46u0hG3o6Ozk7o6xvCwsJcwOlkDDA0MhRVM11dPZhbWKCmpho62lowNDLG1dRkuLh7glQqbJqiEILa5yMxdVt7O0z6kYE3NDaKKhqB86Zm5mhqbML1653SjGVqbgFdHW1pGiOInoB6klTzHDwf2RV43ebGRrmms5sH8rIzhSpFV09fyN+VSnN98a68X96joaEBqHrW3X0d7a2tIsNNTkN+m2MiU4KRiSk6OtrR3NQkpNjm5mby71QO09bRQX1djYD/zc3MoaOrJ4+5+3qXUqpYT08l3TuSn75mbBoLaCygscDDaYHy8gp0drRDW0cX1tbWA6o3kqFGGsMAYash//jtuAIam5qECeGG9DnFq64LAw73BwojUfa+/3maW1pgZGh4U2NyH+V3dHV0ezhluZdxb2tvbxUaSbUAy/14IhqH9n5YVXPOEWUBKpOcOnYEXp4esLG1Q1JCnPCsllVVob29Ez/6yX+JVOeZ0ydE2YQSqmQYCA+fjJ07d4iQgZ+fn6hwKbR04OLiDF+/AOHmy83KhJ2Dk0iTxsXGYObseTe49BRa2Lr5C7Q2NYqsrJ2jI+Ji4+Dm6ozqmlpMjYiEk7Mr2G3Kl5w0WZ988hEefWwdigryxAmnk02Hsra2FjNnzRIVoKXLVoqzSUqVSZOCoKtHR/OGU5uSkiI0X5HTZ+LYsSOy2NVUVcDJ0RGOTi7ILyxAbXWVqFKZmJmJPn1qcrKQdb/w4kuidEa5Xjs7O+GupQADde719RgMdMLZyQWXL11A6OQpMDYyGlHPWjMYjQU0FtBY4KG3gCoz+7Ofvgw3dw9Zk+fOmw/zUZa43tUlew+pvJiwEIdXC2hpacWJE8exdv0GoV+kEzlqlIWoslFBjgmI3LwcjLaxxZmo0wgLD4ODo7OS+UahwOUL57F37x44u7rBy9MLk4KCRcHN1MRUEjikmsxISURAYAgsra2F7Ye0XZaWlkIbRlowUj+mpabA2cUVhoaGoh5KWjEmasj+4+nlKZRflNelWuVQO7cah/ahn/maG7idBeLi4nBg/15MmOALBwcHnD9zCu0dXcIhO87HB9NnzELUqROiR6+tUIhcYE5ODpydXVBSQplaC9HvrqurQU52trz8PhN8RRbw4/ffw6SQUMyfvxD79uwSgQR+Jg6mQgsfvPtPkSmkTvm0adNw6OABibQZRS9cvFQWFmZHp8+cLbx9H7z/rkjr1lRVYcGiJfjH3/+GCRMmiPRhQ32DkGOHT56KiopyfPDuv7Bw4WIsXbFSfqs+YmNjcfjQAfj7+SEpKUkWKAo9uLi4ig1SU1OQlpoqC11YWJgIOZw6eQLtbW1Yt+EJZKSmoLKqSv6di+Lhg/thZWODgwf2S+b4+RdeRGFBLqZMjYDFKEsNI8LtJqDmc40FNBbQWGAwFlA5tD/+4fewfPkKZF67inHjfXD50kVJdIwbP04cWDqp3J+sLEchIzUZx0+dxtp1j8s+lZKago0bn0RGehpMTc3ArCy5yUePHi2JkuUrVorjqXZo//zHV7Bw0SJ4enmLmE9ZaREOHjwoVF7kSScVZFFuJuwdXWBja4uGhgZRMDM2NJS9pL6hEU0Nyqqit7e3SOGWlZVJ0oPVSV09XbS2tKKUXLaOTlj3+IYhT4jc3qFVYzh64+l6skFqfKEy3T2kRx+pvEFIqd4OAzKkg7zDkw0o+ye12zs8wTB+bTCYTX73ZvfUh5JKJRfI23oANqBDm5aWggULFosht375CTzGjEVsTAzmL1wkqinbt2wSZ8/JxRXnzpxGWlqq/H3ytAjJXupoa8PLewy2bd4ENzdX6Bsaw9nFRTK/gaGTZbH559tvITQ0HJOnTO2RR/zo/Xdgbj4KQSEhov71v7//DaZOmYrEhHg8+8KLErmePX1CMqdTI6bjow/eU4otNDchcsZsvPH6X/H0M99Cbk4Oamuq5M1jJEwd7c8//Qgbn3wa3uN8VDriyveEDi2j5Jmz5+LwwX2SHR5ta4vQsMmSjT1y5BC0FFq4GH1WnGpGzpmZVyXzy0g7JuaSnGe8jy+2bd0kv+MC9MVnnwisYuNTTyMlMR4BEwNhTpWZnuTwMFJ99V8v5Enfx/VpKF9JtXxm73P2xy/3kTdV25nkyCpcdf/1+T5j1frcfo/8p3o9U0jQ97XjAbzrg34sX8OO95MyHcz6N+iLa36gscBNLKBaz374ve9g2bJlIsrDbOZH77+LhuY2KBTdWL3mEUm0nI06BTNTE1SWlyErvxChwcG4dPEizkWfw3vvfYi//e0NSbTs/mqnqIsxi0oY2qOPrYWzi1tPde9/f/sbrF23Fo7OrqLylZedhcTEJOQV5MPSYhRefOl7OLx3JyJnz8OZM2dQWlwkFb3UlGRcjD6H9RufwdYtm9DY2IDx431ENCEtPQMW5mZYtmwFLl6MFmc8MDBQpOKXLl8l+41sIEO0Xt3WoaVeL9WNnF1d0dHWJh6+ra2dqEPk5eXByckRNqNtb5DND9EMpZxaXl6u3ChVi6gDLIfcOBfM/prKwnyPttZWtHe0S0Rw4/tDNKi7OA0xJYxIiqm+ZGePpuZm1NXVyoP08PDsg2G5i9Pf95+UlJSIzjIjwa8dvRqOWAapr6uDhaVlX7srFOjq6ERNbY1I7NEemZmZMukZWXp5jbnv93D16lV88cVnMmXGjh0HMxMjkYtldHnmTBSeoxxscgLKSksFSvDXv/wZU6ZOg/fYcdi1YzvMzEyljFOQl4v2zk60NDWhorICS5YuFxEDE1NziWj37N6BWXPm49KFaIEpjJ/gK9KDHh4eGD/BT+6TEraMjGkD4mLpdFLOlhlUYnL37t6FsePGSSnn+PGTmDk9EhEzZuDMqZOYPC0SH77/jtzDrDlzRebWyckFNTU1OLBvN+YvWAgbW3uJyPnZ5CnTcPr0SVF4uXjhAnR0dOHp6Qk7O3s4OjmJk/vV9q2oKC9DZXWNaGnPmDlTVMrSUpORX1iEY0eOICw8HMuWr4CRkZFgfal0tnnTF1iydBksraxkfeC/e3qNuS126/48bAWamholK0FMsrGpqSi7ZWVlw8HBTuR8lVjjkXcQq5yRkYGurk4JNli+o966k7OLZOlNTE3lPWlpaRHC82vXMuHm5iZ/19WlBOVo5OfnCeaNsBQGSD4+PrJpPYiDmL3szEzBgTMQ09XRQV1dnQRg3CNGWZijoLBQ4Ctcx3tESR7E4O7gGsS4U7KTdufaxOpFZ0cn3D08RH++rESpmqcUOBkZh4QzqpiGWTd9Pb0evGJDY5NAjJgNI6k+s3iUE31Q8+FWFuKQGxsbYWJs0hPvNLe0it2Jy2xrb1Pi+g1Hjq0Jy+LaTltyDqjjH0qGU6CAvQqtrS3yGef+kB0qh/adf/4DTz79DAwMDKWH48jhA9DW1RPp2bKyElnnqEjp6OgoMLKEpGTo6WrLu5eecRVz585HaSmrjKNEJtfG2gruHp6orKpG+JSpOH3yGHx8/ODj6yfS7du3bpF9mkkOwuj4HvBdZuLi0UfXYueWz1Fb1wAXNw+UV1RIP4WLi4vsGZyLTU1NGDN2nCiK2Y62QX5+IQyMjODu5orGpma0trXBy9NT1qnIGbMEuubn5y8+xlAct3ZoVXrCVHHgCx8fFyd68np6BCjboKauHlXlJVi/4Skpow6dspACO3dsF71fOn1jxoyRkio3TScXF8GO0OHlhKLc56hRlmhra5FGG20dLVzNuCoPjSVUd0/PIU9rD8bwlFF9/713JOP3zLPfkhf64oVoseeGJ54a2fKiCi385c+vSAmD2Ug6fKZmZiKFRyeKUR4nsKmJiThJZWXF0NE1EAk+O1s7KU+z4YiliPi4K1jzyFp0Xe/CG6/9VYKizH/LwL7+xltDGqEN9Gw4b5qamtHe3ialES6enDdaXJA6OsTR46JErezZ8xaIFB83AP6XTjpVUtioxUYoNkbRQaRSCpuu1CtcaUmJ4E2DQ8MQc/GC4J7oNFLdhZu4GivERjRme/k7Bl89G6UqOOBCSceFTm59QwNGWYySvysXUG00NjXC0MBQ1MTU166pJn73MiYFBgs2icEFNwl+n+ehMgub0dSNXGpgPu+/tYXNYddloTEwoG2MwDmbm5sDW2KcoJBmAVNTE9ngebBpjlF5SGiYjL+xoV7iTM6N4Tg43kMH9kn22NCApa8GCR5LyitRXVmGZStWwrVXJmI4xjjgNRXKJsCPP/pAbBoYGCSbiJaWNszNzXHgwH7BPa9YuRqXL1+SucrKgLm5CU6dOAl3d3c88tha/O2NV+Hg5CyOwvXu6wicFIiASYH333lUKCRLs2fvHplf69Y/LnLRJ48fxfZtWzF3/kJooRtZ2VmwHGWBx9Y9oXxnRsShfMde++ufpTqyfsMTaG1pxj/+/ia6u7UwZepUCVbffvvv+MMrf8aYMd5DuL/dvQG4DmSkp4q8dUtTI44ePSLBc1j4FEk67Ny5XYJjVxdXCZIqKqsQFByMgIBJwzp+BjzJSYmIj4/HjBkzxQnie7p/zy6R82YGkXskkwwzZsyS/XHo/Im7tbdCKnvHjx2Dr6+fSMIyiKRjxjkeOX0GLlyIlmwmx+zp6TVgYeJur87fqWXR1fUOBq38M4N2ZYNxlwSzSoWwbnR0dMq/EUPLPgs2fRnoG6CjU9k4RpgAsa2cK+y9yFVB6LiWcPB1tbXyXhgbmyj398ZG+R73TQZOPC+DaSU+VgsN9fWyTypVx8ykksfvK/fcRmkaZqP19S7lfgQFlciUqmNsvL5y+aK8W2oJ+XuxFX97c4dWtcH++le/wMv/9d/Yt2ePLL50LsvKShExfaZkHdl8smDhIsEEDt2hwLatm8FSsc+ECRjj6YmzZ06LU8tMcWVFlSz8fGA0jJWVNRob6sS4ax5di6NHDgsukQvSrNlzMTE4ZMhS2oO9R2Ywjhw6iNLSUtjbO2D2nLk4evQQxo+jdvH9z04Odrx9vq/Qwh//8DtseOJJwdp8tWMrJk4KxJmoKBQWFCAwcCLOnT2DsLDJcHF1RXNjA86cj5bnxHul1nNaerrMFzpazz73gjhmr/7lT7JRE2Pz29+9AjNzswfwfPqXQHuVbVXpDjpGNzr3e3+uTon0lYntveDS6SPwno4mgfp8iZVZwd6/kVeuj9Ts1xft/p/3SsfIw+l/PsgixuwGsUo3ZAjVT1L9/Vvdf++n3v++1Z/dgBO0t3eI48Qu2d6ju11n7T3NxVv8uKKiUqAVy1asxv79e2URXrJkmWTRY6/EYPGSpaqA+36N4F7Oq0Bs7BWUFBdh3oJF0pxIHXRmbqOiouDo6CCOLLMf3Ix+/PJPsWPbFiQlJcLTnU2Otsi8moG2zk6EhYUjNDQMZ06dwILFy2Tzvd8H5wJx5ufORmHBwsWSCbp44RyysrLAz1ateQRX09NkvVi0dFnPnLnf47rd+bkOHTl8EIcO7heozyOPPiavIkuhRw8dwAS/ANg7OuKD997B8uUrMcGXFZZhhNTIq89KRBO2b/ocQaHh4kAwuZOUlICZs+bAzd1dsP8piQkSjLKKMi0iUqBBrMwM38EO9zb86ZU/yHyoKCtF2OSpsqdXV1ZIoxOdJ0dHZ6mYhU+ejODg0BFgby1s+uIzHDt6RII19jlwDpyLipJ15r//5+f4zS9/Jnsd/Y6x48b3yJEPna0H2j8GOruqcj2oC/fSyO353a1W8YGvwYQJk4d0ZAllu/OjG0QAsPInCZohOG7t0P5b0/2V3/8Wa9Y8gisxl6FvaCipZWZl3Dw9kZ6WhvUbNsLM1HSI6XsU2Lz5S9jY2CAkNFwyX1s2fS7ePyEOzK6RxoKbN7OASYkJaGltRUdrK773gx9ix47t0pFnY2WFAH9/zFm4VGWqB7wgMQvX1obkhHi0tLUKrmXDho24dOmCsgloSIOAIZgN/U+h0MKvf/kzrHnkMcl4b930BXz9/XAm6oxE/+vXP47jRw8hYsZs1NXUSDYs+tIVRERGSnmjoqJCnLziokLJrL/03R9IxvLTjz8UoPuH776N2fMWYuacuQ/AoR2MfVQYwB7eV7XbdpOXXY0N7MES9ghXq3hjb3Lt/pjCHrz6TbDV/c/fc9oBMEi9MaV98JW9HVQVBvNrz10J33lYDlY9iO+dM2+BlL4PHzwAP39/xF65grXr1iszzQNhOkfIDV6+fBmFhflYvGT6yN/QAAAgAElEQVQ5zkSdQmbmNaxcuRpvvvk6fvKT/8I/3noT1TU14pQ/88xzOHb0EGrr61FfW4fmpgYETJyEjGvXJDPLpsfqykrMnDNPMvv39VAo0FjfgI8+eEdw3NNnzJSANTvzGswtzPHJJx8jYto0REefx2PrNgj05usB130d4U1OrpCg57NPPpRqS1d3N5574UVh8Xjj1b/AydkZK1atgZGxCf76f3+S7vKAgInD72CB1ErdSEtOkJKyh6c3MjLSkBAfj4WLlwgUiBWl/Xt3SUMpgzlm5UpKS7D+8Y0DUj49KOsz4P/s44+kTG1taYFFS5dj//79cHZ2liCoqrIC06fPxPvvv4PZs+fCx9d3mOBLvS2iQEpKsux1+bnZmDl7vmQo//rnPwhLzdr1j0uCwdzMTBz2oJAwaA/lO9ffObwVBv12e8dgHvStuGZ7j+lO+mVudt2hHG+va9wWcpCanIQ9u3dJ80xJUTGSkxPh7T0W+QUFqKmulnL/M9/61pBnaC9eugArSysBQxMPyC71urp6rFu3XvAZfEEYsbK8SjxieWkZmNFmRra6tgbJycloamjAY+vWCwZquDbo9o5OwTeysWj1I48quwHr64e9BHRH81uhwKeffCQd8a6ubtIlf/HiecHssMwVFBSE9NQUiUxZpmeHY2ZOrsyPvNxcxMXFwMzUDNe7IeXRGbPmSDnj/Xf/iaqqKglYvv3id6WDcriez0B2YBBSWVkpPLSED9AhsrIZjZysTJSWVSA8PBQZzDyXlyMkOFjgBcR+lZUUwdTcXCAMBMS7uLihpKRIHCvePxfv/Px8yaQwECNshxs854ierg6qqyplbrh5eA6wmCtk8yJ0gdRicczqlZRKZMsGMXLp8iB0QE9XD1evpiM1JQWubm6SQYiJuYyw0DC0tLbINdigRs5BVkC4KLNczzHQjeXirK93Ay92R3NlWL+kQHZ2FrZv3SwJbNqH1DCkGyNW/cmnnpa5NlKPnFw2/NXA338iXnnl9+JsBQQESDMfscvnz50VR8DdzR179+7G7NlzZI6xspEQF4ew8MnyXBPiE5CVeVWcMz7z+55RFMhBMd54/VWx89y5c9HS2i78lYcPHZRqFCtTp06exNSIaYI5F4jNSAiWVAFOXk6OZDktLMwETvenP74i5fxVa9bAy8tboCzMzpLx5L7b8w4mKNeZ9NQkGJuaobioCB+99y6++8MfyhrMg42uhBaFT52G3Tu3CWQvNTUV64bZoWUJmuNhlUFP3wDzFyxCamoyCgsKpQenqDBfnEWW9UtLijFlWuTAfRt3YKMh+4pCS6AFly5dxCgLCyxbsUrgVSy579u7B/PmL5DPuJYTkjBj5uwhDCIVyM/Pld4HVqItR43C5KnThD7rRs1NmTjh68RqdFVlORycVKwFMluVAa38bx8hIeVM7mmB6TWzuzrapcdnlKX1gPdy+tRJ2Ru5lxHipoShdcs+xnEwQGRw4uhEOrAbQkLyR+VV5X+LCgtkLbCyVq7Lyn+99+O2TWF9QSEDpL/vV+fqgMpF/R5Mz/1/vQzbpzQ73Atob7UP9ZiHe0x3Ond6d/n2ZLnUb4dqEg6YARxIbUuVeeyfLRthtqiursHhwwcl09TV2YnFy1YgJztLsGtcUCIjI3EdCuzauQNLly3HtMgZEmRdPH8Ws+cvRH5uLvbt+QrPv/g9bPryc8QnxOOxRx8Th9/YxEQaCYg/Il0Yy7XsEA0OCZOF/cL5M1IiZLPPjQ2UWMs6KTUzA7Nuw0a8/967sslWlJfC19cXc+YvFEqUpMQ4uHt4YfdXO8SpptNMCpXG5lZhSSAmq76uFuPHjxfasakRM6Tp4cjhQwgMChJ+w2sZacKPy+aAh+boySqoGkbVS/n9Wp+G1DC9m1xVQhnqd6r/u3XLymKvd26INog7us3+TAB93m/V2jzC3nHl9Oi1y6vH97V7IXMLjT40G+4d2fMWX+JQ2FBLbCQdC0JV2HBnM3q0OCDMHJLUng2msTGXUZCbBb9JwYLvHM6D42YQXpybBZ+JgZIUMTI2RlxcLLo6OuDh5Y3khFiBEArPqeUIWHsUCkmUJSTEyVrLtbGhoV6cNTZLs2JCOE0Jm4l9/eQ5DOVBSCcTeVnXMrBk+Sp4eHihuqpCHGo2l48b5yP8tMT0tre14FzUCcxduFSahulYcn5kZ2dLYpDzw9jYWBo2Wa0SOspRlrKfuHm4I4cQoY5O+PpOwNGD++HqMUbghcoeD7VjqsD3v/cdCagJc1q1eo0E2sT7GxoZ4drVa2iorxOGHcIUWZUtLMhHTU2tBCteXp5ISU6W76txuPx/Ot7cj5SMB/d23N6hvbfza36tscBDZwGWd9/91z9x7Mgh/OznvxQxhgP79sDBwR4uru4CgueGkZKYiMXLVwhlVkVZGfLzchAUOlkyradPHMPcBYsEY8xOajbFEDJDwYSMq5nQ0tHGlClTER8Xj/379ghjwCOPrcP2LV9Kxymj3xt0JgqcOnlccFtcnCIiZ+D8+XPK65YW4/nvvARXVw8B2BOIb2k9GsePHUZERCTiYmNlIaPD+89/vIWlS5cJzo6Y8+6uLrh5jpGN/b13/iXZkSeefAoZaWmCaQsMDhkBZb+HbvpoBqyxwH22gCpIGMgh742xV2iJIqD+iMmK9x6P0kQME1jS19FmdYhYzPYR1ig9EGynd3DTL7kzlE9eoYVr6amIuRiNR9ZvxJ5dO8WpTkyIQ3xCAhYvXoqszEyBtflO8EFSQiyaWtvx5JNPSfWNKpDkNZ8cPlkq2qywJiTEw8XZSZpQSaHl6OyCpsZ6yYpfiY3Db373v4g+F4WW1jZJstCpVWZaJQLET370fcyfv0DZZN3WjDOnT8PByUUgMKzMkOnm6OFDmD1rFmbOmY+vtm1C+rUsaYRetGghXnvtNURGRAh7CxukGeSwKfOxtevg5OR0z9bTOLT3bELNCb5pFiBtEhsB/Hx9seurnQgJC0fclRhY29gINrOyrAy1dfWY8O/PJ9Lx/DcGj3R2jFqnz5qD2tpqnDx6CHPmL0FU1CkRQSCWbc2j6yT7ycYHYo6tbayx5tH1OH3qBKZMixAYwM7tWwRmw85PZmKYyWBWlc6oo4sLGuvrcb2rU6AFLIHt+WoHJgYGichBbnamsE94eo5BfHysRM0H9+9D4MSJogIWfeE8fvDDnwhDAeFCpaVFKC0txxNPPo3o8+eEP5cUV+mpyQKNIazkPqMwv2lTR3M/GgtoLKCxwNBYQKGFpPhYUfDa8PS3cGD3ToSET8HJkydw9do1zJw5S5qxMjLSYWdrK4FAYlIylixdCjLfZGdloa62CstWrsH58+eFiYhMEjOmT4eRsRGS4uIw3tcfe/fsEo71w4cP4+WXf4qC/FwUFhVJ30xwSKiw35CZgA7t9156EevWrxdKy61ffoEW0nCNGYPcnGz5LuE5H73/HsaNGytMK5s//QgBweG4EH0e48aPR0dnF0qLCtDU0iqCQWx+ZdZ41uw5Qjhwr4fGob1XC2p+/42zABsMC/ML4OrujqKiAhQVFsJ2tK04iVwo2KlbXV0lJXnCBOjQMqsbcyFasGvM4JL9g78nxpGsEKHh4QifPEWUXsgjmpKUJFzJYZMn93ArV1VVgpj1sMlTBGP01fZt+PFPfya4LcId2HnNhkhSoBGTFhgULNRfV69mSCRNXCXxdcwis1EkJuaifIcR8JGDBzB95ixZNIg3JSvJlZgYODs7YYKvv5JSRUUTwxKXh9cYoWbRHBoLaCygsYDGAsNgAYUWigvzBcIWHD4ZaUkJAgU7fvyo4KTd3T2Rk50pGXgXVzdcOBsFW3t76R9wcXPD1YwMyXoyUUIJW/KNkw+d/Rys7hUXF8LO3hEXL14QJcrWljZxLKmaSYjb8lWPCA9zbV2dsFqxILB/7x4sXLQYWto6gpU9cnA/DA0MYGRqJjzUlqOssG3LlwIrYF8NezvIYkGJeMIYaqor0dLcBOvR9qKemZWRJjy1hO0NBWRD49AOwzzVXPIhsEAv0YivjbYP49eNv5DLlhyARkbGvRD3/XB6A+GHVf9WU1UpESwFD+iokobOevToG+D6HpzfQPhkJc5JFqbW1hvCIv0HPxDeuZdYCRcbZpONjCmlOzJwgw/BbNEMUWMBjQU0FhhiCyihJT1wesmRKkVkmNggBpmUfsT1kimCzfNWNtZoaW4RmBmpFTs7yGuuhc7ODmmgNyFOVbWPqOH4ZIZhUyq5YEnSwP2DByt8sg81NPTQHvbZPshy0tAgwiSjLCmM0C387HX1tcIxy33E1NwCzc1N0qdB6s7mxkZhpJIeEQXk72xIJrnAUOw3God2iKeg5nT/yRYYqDlxEPYQJ5rf/zpH7iDOIo0Vd0uPdC+/HcwYNd/VWEBjAY0FNBYYjAX6c4rfKffsQJzqvO5AHOW9zzlQQmMgXtz+3+tHqdADXOs/3ttdazC2UX5X49AO3maaX2gsoLGAxgIaC2gsoLGAxgIaC4wgC2gc2hH0MDRD0VhAYwGNBTQW0FhAYwGNBTQWGLwFNA7t4G2m+cU3xgK36+G/VSmltxHuBGt6O0nB3ue72Xfv9Dr9S0zqc9+qRHWz3/T+7TfmwWtuRGMBjQU0FhgGC/Qvx9/NEHqX/e8EAjDQNe6EbuxWELrBwuvu9Pv9741jv5N9T3mPGof2buaT5jffCAuwU5SKX+RcVYLaIewF1KMm358IC/Rq4iK3n7aWFvQNDKUL1NbOHqWlxbC2shZmg57v9iORb+/oQEFenpBJE8hvamoq6kQkmyYVGKU2ex8kuyYwnyIMtbW18n2C80eNshAmA+WbO4A8LZWbSophZWWDpsYGaGlrCx9hc0uzdJ06OjgiIyND+B5tbe1hamaG9LQUOb+zi6sojLV3tIuYBEm5eY+kZCHQnw0CI0Lh6Rsx8zQ3obGAxgL/eRZQIC8vVygTnV1cYGVl3VfBayCD9O7CUjXvNrc0yR5F7lfuC9xHTE3N5FxNjU3y91FqYYqvCZooZG/JycmW35PxoKdvo9dex4ZkKpQZcd0Xn/KG6ldrC5ufu1Wf3fj33t/pfSv8PnszDA15rl7fH+B+W5tb0NnVKTy1ZP0xMzMXRoaeMdxm0mgc2v+8t0pzxyqHkHQor776FyxYuBi2tqNx4fx5ODg5Ij8vT2i6Vj3yKPgy8uUnc8Frf/kTZs6YAUcXd5w5cxrh4ZOFY3bJshWiqEIeWsrkko6rt/OXm5uL7du2wsvLC5QO9BnrjY6uLoyyssblS5fw2htvgXK7lBWeNCkYb//9TVFNGTveRz739PSAjbUNQsOniGNZUlwsz9DewQHorYSl0MJf/++PePqZ53D21DGRjjwTfQHh4eFwdHQW+cS33noDkydPRWV5KVzdPHDhQrRci9r15L9NjI9FdU01crOzUV1dDQ9PT1HJofM+FMTXmsmnsYDGAhoL/MdZQKUW+qMfvCTc4qNHj8ba9Rugr6evFJbQ0REqLGnm7b4uPOO62trQ0tEVWVttbS1JZpCR4EzUaWERCA0LR3NjA2rrakXqmnlMCiaIfLqbm7Ab6Orp9dmLOru6EHXqJC5djkFrSzM2bNwovOW8LFkQSAfJ/x4+fEjGGBQcKgwJ3N86OzrR2dWB1JRU2fco8GNkZIiO9g5JClFFk9+lFDCTPjwfr5eakoTy8nKRBmbih/fDgxLInR3t4uzSG9fW0UZ9bQ2am5phbWuH1/76f3jmW89JYol24T332e8GmEQah/Y/7s3S3LA6w0mVlXfe/ruoY1HlZO/evUIY3dneLhGitpYC8fHxmLtgoSwYmenpyM3JwpjxExAfF4vammqhSyFHX1t7K95/55/wGe+D1Y88JrKC6lJJVnY2tm/dDP+Jgbh47ixsbUahG1oICAxGVlaWCDhQ+SskNAyTgoKFH5Y8tG5u7khMTEB7extMTUzEoWVG9713/imUKE8/+1xfiVyFFn7xs58iJCQEGcmJou9+OS4eq1etEue5s7MLf3vzdZEuJN1LxPQZskhSrz58yjS4urli3+6v5J6srK2EP3DTF1+IE8/Fx3/iRI3Qgub10VhAYwGNBQZrAZVD+/vf/ho//8WvcOZslMjNkkeWKl4BAVxbFSKaQ+8yIzMbxvp6CAoJwebNmxAaFIS1Gzbi/PmzwmWen18Aq1Gj8PQzz4rIwpWYy6isqEDkzJmoqqpC5tWrKC0rw2uvvwlLKytVhlULleVl2LZlEx5d97gkachJXlpSBB1tLZiYmOLjTz6Bo4MDzMzNpIqXmpYKdGth4cJ52Ll9m8jUuri6iphDV2cXfvWb3+K9d99BdVU1Vq9ZI862tq4+Avx8cfTIQYy2cxT1sCNHDqGtpQV/+NOfsXXzZmRmZiEiYiouRJ+TbC/leH0m+GH+/PmIuXwRcQmJSE5Kwq9++zscOnRIxv/EExulcnqrSuEdOrQ3w2zcCQ5jsE++9/fv5vx3itW4l3EN9re3k88b7Pnux/f7j3EgSo27eR43G+tQYInuwQ4KBbKzMvHnP/4Bq1c/AhsbG5w8dRKubu6ij01BAoa8FDQYN94Hfv4TUVFWilMnjuLRx5+Uf09OTIC+nh6KS0owdpwPTp08Bu8x3li4ZJksFlRYYWRJp/XLLz4TZ9nLwxMZqYkoLa+AQlsHAf4BkvlMSkoUtZfJ06YjPz8PFy9ES+aXymAnTx1HQ20tKquqsGDRYkSdPi2O5drHN8DUxFQiWz2WZf4tdfk/P30Z4WHhSE2Mx3gfH5w+dx5zZs+WDCvLUm+88Rp8fCbAdvRoEYHYvXM7PDy9MHvufIl+33rzdRGOoAY3IQ/nz53H4sWLJep2c/eUxdZAX+8eDH8/f6q4wUTT5zJ3jsG6n6O7+blvtj70ft8Gel960+4MPQXO4GwxEJaPZxjucd3qLm5m05E+7sE9Gc23R4AFVA7tz//ff+M7L30XV67EIDvrGtxc3eDm4SFZzujo8wIXcHJyluocndTi4mIEBATAzsYaY8b74uCBPcjJzsHsefPR1tiIa5kZ0NHRg4eXl2RF09PSkJubIypiTJKsf/wJEVbghsHSPTO4X23fgsVLV6KxqVEqkBcvnBdVysjI6aisqISbp6eokVWUlQsn+rSICFy+GI3WllZMCg7Bnt27MGvWbOB6J7S1dQSawIwyM69FRSVoamoSQQXeh7GpCfbv24/5CxYiPjZGqpqJSYly/64urnB1dYOjg70kkEqKS0TBLD83B74BE3H8+AkotBTy7xz7hieekCoi99yb0VLe1qFlVqdEcHlWgv+j2gTJdI2MTZCSkgJ3dzdRrBgMcPdOpldJSYkoXRAH6OrmBhcXlzv5mRiTD8nK2vrG97+GI7mjUw3Jl1giYMk5LydblDQY1eTk5MBnwgRJ6Y+EgxHitatX5Tmz9MFJxiiMZMuMnMwsLGSYtCsnvjVJkdVHf7L/3jc0EIk/IMTPxGeyjEF8KcvpcvTZX+6zE6JQCL70b2++AS+vMZKdbGtrxezZ85CVlSklFZbmiWFtb2sRRTBmZOnEzpw7H5cvXoC9vT3S09MFLsBsJ3GrFuYWUGhpicY28acssRQVFSE1NQURkdPFvtFRJwWz6+Dsiu1bt+CpZ7+llACsrYajgxPKKiqQkZ4mymKUyE1LS5PSDLPDK1Y/KgsIo1QSVSclJMgiQKeUL/lnn36CpcuWI+HKJSkBnY2OhpWlNczMTOHu5o78wgLMmj1XpHxbWptx+OABkd2dM3e+jH3v7p3w9PJGQnwcGpuaMH3GTJSVlsDc3ELef+JpKWE41O/7vb4HhEdQ1lFfVw8mZqaSyY6LjRNlNJbfRuShUKC5qQlxcXESMBgZGsLczAyl5eUiq5yXmwtLS6UaHddcroWsDEyY4Ctk6ny+xOKlJCcL/KS0pEQw4Nw0HqTKG6Uribmzd3AUxbnKygp5Fp4enrC0tkZsTAxsRo+Gp6enlEFHykGFPcKLLEaNEptyPbp44QLa2tvg5+ePgoICsWdISKgo642Yow9+nkGcCk/fs372Ci6Gce/rYy81PrP/ntDzd9WYe/+9N5xquIyvckTl8urx9BHHuUNbq37zt9dfg52tDSoqqzBv/kKcPH5EfCu+47nZWTA2NYezqyuqqyqRlJQkcAAHRwdYmJujoCBf3nXuHXT0bKytYW9nD0q1V5Yp330nVw9R6PL395fs6owZs0DBn+7r3XJerjOHD+xT4WhzMXnKFPl+c1Mjpk2fgV3btsjaoWtgJHtVXm62yNkam5jiyP49CJg4EY0t7QgKDkZ3VwdMzSwQd+Wy7KUTg0KRl5cjYgncz7j38Z1i4sbXzx+FBXmyxl27dhWVVTXw8PCAo6OjJFdMzc2Rn5sHPX1dFBUUiH+QnZOLRUuWIjU5WQSL5i9cIufQ0dWFr6/fgDPi1g6tQiGp681ffoZnnvs2HByd8Oarf5YTTQoMEoezobEBG596VglwHkQ32q3npwLbt28V59Rngi+sLC3R0dGOpoZG+E2chJKiAok06NXTmaD+fFFBvhhFW0sbmZnXpNGGm4WvX4BoHA/LoVCgoa4OX+3YioLCQoz3mQA2/NAxMDYyxux5C0ZEtqur6zrS09Pw5huvYtGiJXB3c4O2ji4Uim7o6xvIc5CMo6Ehsq9mwMPbGzVVVfAY4y0LPZVCcrIyxfnzC5goG2trWyvGeI+VDaO6skKk+aqqKlBf3yAZxfPnzmHu3HmSDaXmc3Nzi7xAOdlZohpC2Vg60/fzuN4N1NXWCi6JL5+ujg709PXQ1dUF2kRPT1fpY6s2DJZGOjo7JEJsb++Arq6OjJv3Y6Bv0OOQE6jPKNPVw0MarRgwEH8k51Mo5LeCCdLTFRA/gffKdVO5Mcn3O7sk68qxKVVelNgmOq8sTakDAErlUkLQ0clZ/rW5pVUyw1y42DjQ3NIiMolsZjM0MpSFTRlItMu/M+rm+E2MjeWZX8tIQ1tbO9zcPeRzPvMrMZcku6ynoyXVHgs20I2UjRIQe361YxuMTEzg4GCPaxkZMt/KyspRVlqMpStWSqAwdOvTUM1KhajobN60STaEsPAwcViJbeZYd+/6Shb8Z597AadOHkd7W7usdfp6Ojh46BA83D3w7PMv4E9/+B1G29kL1ozvzMSAifCfFPhA4CG0/aYvPxeFuieeega6Oro4f+4MkpMSZY7b2tohLzcHo+3sBKctjvYImDscAoPMlOQkNNTVYs1j6wRz/sZrf5VKhq2drazdljaj5d1ZuHiplGWH++CaxRKxgSGx9IXY9MWX8tzXrn9cAoqzUaeQlJiINY89hqgTx5Gano7I6TMwkxm1YbO7Ajk5WWhvbYGLu6eUvNnsQwlV2pwB+55dOzF/wQIYGplIUM5mpfUbNsLI0GD4TK5Q4GzUaezfv08qaStWPyIB2cnjR5GcnIyNTz2N82fPIDk5SSRjw8KniNLWrY6GxibBltIhZYmfSZKWpkaZZ1ybmQzhPlhbXSnrMROHWloKWcsrykthaGwiNmuor5N3ycTETPakuppquayp+ShZO3gO2UP0dFGQnydLH/dUDq+ltQ21VZXQ1deX858/GyV77qSgINmruZ+bW1rLvXJ9YjKF+9fh/buxZt0TMi5lo1a3+Fvc17lXjLK0Rltri0Dk8vPy0dRQJ04ux8skDO+bA2DVkfNYYH3aWtDS0ha7cc/lHsim5Pq6WsH/Ur2Mf+aeTBgfez/q6uvh7T1uwPX8thlaZtNiYy7Ae/wEREdHSxaK2I3m1jbEXIyWl/2nv/i1Uu5zKB3abVskNc3I2dXFRTZVCwsL2Nk7IDszS7rLjYxMBFBt6+AAU2NjXM1Ix+NPPIljR4/KWPhZaGgY/CcGDeHYBvF+KbSQn5eLN19/FR4e7mLDWbPmIi0lUSbntMhZ4hQN/6GM8v/4h9/jBz/8Ea5cuSyL4lhvb1RUVSEpIR5uri6YFBiMvJwcNLW0orikWNL/jDLZWX/s8EHJzFjZ2KKrs0OcNCdnZo+S5OV1cXZFR3srdHT1EH3+PGxsbTFx4iQ597hx46GlrUBKWjoM9fUFrxoaPlmcEsWQzakHZ2WC3PkCMlt1t4pddzpaOruyIAxV5kvBTbu7z+ZHR5rXIPBf6d/f30DjTu9d/b3y8gocO3IQS5avwtEjh8SpmjN3nsBCvvj0Y/zqd/8LMzNWGe5z1n+wA1cFS8zQEs4ya85cycKmp6SgtKQQcfGJgp3mhlBXXycSlD9++afYvm0z4uPiMNbLC6PtHcRZYGA1Zeo0BAWH4PSxw1i4dMWN7uC7Gdcd/oZzIzsrS7JHU6ZFShB29sxp7N+3R7JK/gGTcPTwQfj4+ePxDU9KE8mIORRaspmz+5oJGs4PZpq//Pxjcay433iP88HxY0fw/Le/IwHvsB4iNdqIjz54B9MipkuyJj8/V5pZ5y1cJOvN7379K2x88klhUSGEat26dXBxdVcytgzTwSal9/71tuwXcxcsQszlS0hLTcb8BYskQNu1Y4uU55hJfOKpbyE+7goK8wuwcMkSGJA9ZjgO1RqXlpIs715cbKzM35aWZuzfvwfhYZOxd+8eyTjSuQsOCUVgcMjgkzADrLeqRfbrAUjv76ozx32yxsqGsv4H9yJK5dIx7jlU98deiuKiQnkOTHQQttZ//VdLqnPusRfj69dQVwlU11YoxE+UBJEB2XH6jelripgDPODeVYhe3xclS+51NwnObuvQMluTGHsZNnb2+GrHdjg4OSM/N1uiQVd3T5w6cVw60RwdhzIDosDWrZtl8vj5B+B6ZycO7NsDW1tbjLKwgIGhMfRofAAdHZ1IT0+VzGd3Zweeef4F7N+3T7x6EyNDabiZtXBpP0nRB/SGKBQyWXbt2Aa/gEDJvoRPmSIL/rwFizCejtxQOSL3eksKLfz217/AS9/9vpQEmKVgtJaTmyvRFx1aOpdX0/4LD2sAACAASURBVDNQXFwoHZnMljc0NsPIUB/2o23QraWDM2eiJFvDzYxOraWlFQxNzFBbUwXCSPgClZWVCibV2dkZuTnZEtXZOzpJhjc78yrcXd2k/DHOh2WF4XJCBuO09ZOq7VlsbjZ2Na5wIInbW2HAB8BUyrV6O6C9f3+re+g/hl4TaCBKsHudX/fx94zYd+3YDv+AiSgsKhK4xOIlS8UJP7B/D1asXI3x432GcS7d+uavXLmCwsICqY6w4SM2NkYgIJs2fYFvv/AiPnj/PdE/Jy5twaIlSIi7IlmK9rY2qZSw8lNQVIhxY8dJBzUzIzPmzJNkw4M48vPzBY8ePnmqlD3JlMH1gbhwZmEsR1lKBmb6zFlKuNKwZQr7WoN7x6t/+RO+/Z3vSbVER1sbly5eQF1tDYwMjQS/yGZPHT19PL5ho3w+3AezbvFXLsHC0hKeY8bh9IljUg4OCQsXONimLz6XPZL0UIR5GOnr4Tq0sObRtX0dmgd4I7QzG32IsYycOVvgVOfOnJHKCekEDx86iIzUNJibm+DxjU8Lg4yXl7dAtoZ7rvA9iz4bJY7qjDnzpbFp25YvpewtjbwhoeL7EOJIRoA+TuMDtPEtL9UD91B/q9++1OMw3uRzpYet6k/o/dtb9dQM9P37b5DbOrR0ZvJzcmBtaytpbOIoszKviiefnJIGezsbRM6YLZHK0DkfCsTEXJIObuI5iWdk5oVYrUWLFksUzVIsLdx1vUvwiizZ6evqYGpEpNBYkG+zrrYOy5Yvg5u71xCObXAPhZAIloHYlThl2jRZMLlQBgYGCT6R2ZeRcSiwZ89XmDlzNsrLy2BgYIimxkYBmB86dFAajBbMX4iaqkqkpacJhIJllvE+vmhsqJcSRkfXdfktM0mkfpozZx6OHtqP9KvX4OnpJTysLNcbmRgLXQkxqCamJqivq5dygqG+Ho4dPwp7OwfMmjNHcJvDcRDgzgyHnb09Dh04INRVxCplZmUKHjYoKBBZrBKUlSJwUiDGElPa3S30XsRDpaamSSOYne1oeHh4Ijb2CrzHjhXoTF5ePnz9/JROP7FQqjnM7AoDuLrqGnHuv/4uKZCamizZUXaNXr54UQIDOm1Tp02TpjZG0oTZ8D1lSYyByeTJk6XcczH6AkLDwsQJIjaWpezCwkLBRHHspFfhGMjw0NbeDmNj4xGXib3ZXOBaQAz4hfPnJMNpZ2crGYfY2HhpOGAQaWZqOhxT6Y6umZuXJ6VHP78AYbBobGxEwKRJ8iyXLF0mFY2Kygo4OznjSlwc/Cb4SJbCyMBQnAMyYzCLVFRYiKLCIixfuUIgKA/KGaiqqkZlRbn0OpCVg6XQ2CtX4OnlBStrG3HSCQVhVnHYMm5fexIKNNTXSh/IxMAglJeWCI7xq507BP/Hyl56RppQIBGH6PYAIFB3Mlk419NTk2XfoEP75z/+Hs+/8B3JwLKhiPtkeWmpYMi5d48Z4y0l8UfWrh9Gh1yBxIR41FRXIjhsMi6cOyP45Jmz5sDS2gZbN30u3NkZGWl44slncOTwASxbvkrw48N6KBTYvmWzONir1zwG/4AA8TOYYS4sKoCvr79kyNvbO+Hn6ycB20h0aNnDc+nSJZibm8me3cPr2su4ZaVlUmEdPdoGxsZKvDihkbc6CFcrKsyX/WikHLd1aDnQLhWtgtqRV3KVdQuY2NDQQNlhPcQHI1Eu2qROYpqZTgZxgcSdkLKod5xAzAWbi4jHIFeZEqfYJi80MZ73G4t5u1tva++Q8ZgYmwimkVAIdgcSHzSSyreCC9XTFaymOs9Hmo/YuLgezjnGEVw4iWlmFkNHh6XobgkwJMZQlduJ6+Hn77zztjQ2rVy1Go7OLoIT4jX4G+Jv6IDwz3xGzFYTr8t/47waTI70ds9gMJ9XV9fg3JkowfPSkdiw8SmhKWHWw1hfXxxSI1Nz7PpqByIiIjGdQUBZiTSKkS2AAcvJ48fEYScGiQ1LfM7WVpZwdnVXOvb6+ggKCZMy25moUwgLmwJjE2MkxsXCw3OMkmqlZ5YrxGFhd2pJSSmef/ElfPHZp5g6LVLgK5xXy1auFsEEBk8BAZNwYP9egeekp6YIiwLxUqWlpTIWvrs+Pj6wshyF8KmRAiU4eviwOH7E/FJsgeXBEdUIc5sHyLlHR5BziaUzOud03A0NDARHNpIPYqY5fmI0G5uapQFCR1tHAhOOnWsh3y+5p8ZGSR5wPvHvXPf4DvIgxrajZ817cHesfPe75f1lAM+xc50jvIBZYt4TN9GRxo6hXrO4x3R00ubass+wikS8OTvPZQ8xNRm2taj/UxSu0YpyefYMiKPPnEZQaLjQPRG7z14IVsKYCWV1kM2fdLSU8K3hOxh8M7tp5+gkPKis9pFJhgE5P4uLvYKgoBA4urjgWnoavMeNV5bAh/koLChAWXmZiOcw4821m+8cn4HXmLGCY66trZNgztKSVI0j6+BazyCnqrpa3kU9fX1MmhQoyY6IiAhZd5hp5rrCQGju3LlSZWVPlPXo0Wiob0BgUKBAFrjv8xyEGxLvSijoof17sW7jUw8seL6dde/Iob3dSTSff4Mt0Ls79W5uUzA5KqWRYYMPDG7gNbW1eP3Vv2DXzm3YvfcgamrrsX/fbujqasPLYwwmBgYLb+3RI4ex8eln5WUuLysVTsGwKRFS+mMpkJvK2VPHMdrWHvX1tRht54ArF6PR3NoOi1EW0mG6c+dXsuAsWrQUzz73PDZ9/qnwvQYHh/ZxaEmtcvTIETg42Al27sjhw+KwEa/83e//QBqJYi9fkGAkIDAERw7uh7OrCw7s2wsnJxeh+3r3nX/KIpaRlibNXszyTJjgJ+Xqf/7j74ID+9GPXxY8JAMw4h8fRgzz4J625tsaCzxkFuiNQVRjHuUWermsfdgE+mLih+Vue2M+1XtCr4C9Z0zEW/JzZXZkWIba56I9Y5VNTGVj1f+rxzqC9zcmI08cOypJi6rKCjQ1NcPExAiJiUlSQWGDV2NDHVqammVP8Bk7Bll5heKwEzJYV98gLAtkQaDCWeT0mTh85DB0dbTx6KOPSYVozdrHNQ7t8M9UzQg0FhjYAuR7Pbh/n9CqZWVdg88Ef8RcuihqYuMn+KGshNi6NqH7olgCF1/CYpjRZTMbuQDZDDhj1mzBT9PJZIZq/qIlSE9LlXOR7cHa2gozZ8+VphOKM7A8uHXzl0LZ5O7hqZRIdHaRbPiH77+L1vZ2ycI5OzsJ/Ia0Ygf378HipSvg4+sn2Vh2vwaFhmH/3t3S2EfsYsDEQFjZ2ODUiRP4/g9+KFkcls5Ix8VM2rwFC3EmKkqainhdKrswO0iGkeHM6mjmp8YCGgtoLKCxwN1bgGwChw7ul72BVFs+Pn44dGCPiC5UVdcIVeNzL3wbly5dxNX0NAT4+mCUja2IGrCpi9l+1mtbmpvRUFeDR9Y9LiwUpNwKCgxESVERVq9dr3Fo7/4RaX6pscD9tQDLSsR4ETeXee2qQGuYzSzIzxfMdmhImJTura2tBavJyJ1/T01JFmUXklPTiSWXLzt2ExMSBGcUFj4ZaakpEvmymYfQCnZXNzQ0iogBKcyUjYNT5c+nTxzHE08/K4sJ+W9JNs3z8hzsXCVLBLG+1Lxm1pZ5AzbVEWpAHlA2Grk4u0gjDhul3N09MIH8mvl5AhOigAO76MeMHSelVkIXWDIm3y0zvsxCaw6NBTQW0FhAY4GH0wJ0aONiLgmlIZtH2X/EpAlhmgZGhhhtY4u6uhqhx2IWdoynJ1raO0Xxy9TUFKZmZqgqLxMVr7KyEtkXsq5dlZ4XSu8Szz19zjyNQ/twTg/NqP9TLMCFgNlNSv0pKbi0hFGDDiV5jYU+RNHDCCsVMnK7Et9NfCx/x98Tw6TEOeoIRlLZfKUj5+FB/J4cCoXQn5H+zszcQnS26Viz2YPnFgyl6rssI6l/y+uQ34/jY8mxqbFesq6WltaCpxT8qIytQ5xyGZOqkkesJnHMPSxcCgXqa2v/P3tvAZ/VlXUPryfuLsTd3XAJbsWhpRSoy9THOv7OdOQ/3zvWkU47balQoUgpFIq7BAshRCBC3N1d4Ju1nySENJAACaR97/3NtGly5dx9j+yz99pryXVkpxhh7Fz/V7qe8p6KBRQLKBYYMgsQ+yq859rq2pX6hgbBiZNjnr8jRI7UdfwbaUS5RrHgS9YHLa4fV2VdYu0P65qI1eZaQwYTZg9HTqEnoGBoh6zbKDdSLHBdHOGObPENnsFu7PFt3G1IMM8jAHN3G6+snKpYQLGAYgHFArdhgW/wvPZD5dX7diOEam+gN1Qc2oEspPxdsYBiAcUCigUUCygWUCygWGBEW0BxaEf051Eap1hAsYBiAcUCigUUCygWUCwwkAUUh3YgCyl//w5a4BZqXP2mYrpxrl2muO30y63Uv7rueQOtDcG7XSmg7vb0pb0ZDlqbb5lC2HewYyqvpFhAscD/BQvcLTTsbmz0HZ7nFYf2bjqGcu2ItkBLa5u0j4B4ks+TKJ2VTvxvVvl3zykkiSY/FYu+yNdHcQ4C5EmqTmWz1laC4CFFVc1NjTAyNpH/ZkEWeVrVrqf6574HCdt5n+7rKQ4iBWWAFJd1C2tQnYi/19LWkQpUbR0dKRzj+QLmv6q+j66eHlqaGqGnbyAKYEI3iWsgOb/odffDs0WQv4iLqDSkwI0/dreJ9yZxP9+bohe6erryTHV7deXeLCJjW4TIv61VCtzUsqpqeUMWpfGm91vAZER3RqVxigUUCygWEKGqq6CIkcz3FE/R1uqxS0fnVZlb+xbkSjFxVwEvC415dKuSsUiY5w84/6rUwics9uJa1p80NtcTto9Fxv1RNra1dxcaD44jeLDn9y585lrDFbKnYPo2eo3i0N6GsZRTvz0WINXWX//8J/j6eEs1Jqmsdu74Cn6+vlLlSaEBe3sHUQgqLy0R2pJ/vPFXoSrx8vIS+cuSkmL4+vkLzRUHeXBwsMgpT50xU5zOnOwseHh5C8VWYwMJqJ1vlD6kdOLmjSjIz0NzSytmzpyFg3t3wcbOQRS/nn/hJZhbWojEcG5OtlCAHTp0ADVV1fD19xfWg6KiQvj4+GHUqFHIz83BKDsHmbxCIyKlDWwjuWOzMjNQWV6BqLFjb6BQIbvB0f174eTmBmNjUxw7fhTOzi5CA2Zhbo7g0DDhIOTkkZSUjGXLliMtPQ3NLS2YOm06PD28kEXFtPIyuW79h+uwePFS+AUGid2MTUxRWFgg1GLkwh1wUv32dCGlpYoFFAsoFhhaC6goA5wgSo4GhkYIDgkWER1KLNvY2OLcmdNwdHKSYIKpqak4nuQcP3hgHwKDgmFnb4+a6mp1UEZHV9YbStZSrpb/TRVO8qf3lb2m+1lSXCyCPFQNGzM6EoHBoTAxNhEnt7GpUVh1yEt77OhhoZNkoIP3unrtKqqrq0Utbd26d/DAgkWwsbaR4AjpKqmQRie5trZOrZamUqs2WllZ49//+gcWLV4KG1sb4VDne5qZmYrqWHNzizj0fBcGbLhmm5qbi32ohujj64eGxgbY2o4SIYfBHIpDOxgrKed8yyygkoHz2o+/j5mzZsPMzAKWFhZ4773/YMKESWhtacaMWXPg5OyMy5cuieSl7ahReO+dtzFv3nzs37dH+PYmR0/Fm//6Jzw9PVFbUy2RUg6useMnIjkpQaRvV61eC19fX5GYHD12PAx761+rNPDWm/9AbV2dSNxGT47G1s2fI2LMOLS2tmHVqtUwMTMV/lpGhymYsOGT9fD09kNi4kWZYJ773gtIiDsHY1MzVFVWIjMzC26eHvDx8cWF8+dx/vw5PPr4U3BxccahgwewZNmDQrPSffA5G9avQ21Dk8gectLw9w9ASkqKOKi+fr44dOggLMwtQJnj6OkzhSrs3NkzwqMbFTUGRw4fgqWVFVxcXLFv907hv4WmFrZ/+YVI6IaFRyI29pxsEowG0P/+lnUkpbmKBRQLKBYYOguoVDh96pTM1e7uHvD08hSJYgYuwiNGS/CEAQ7SYwUG+MPe3hHnL1zAiWNHZb1ycHAQp7a4qAgV5eXo6OyQwAzXJ2bWGORYsXKV0C72lk6nA/n+uncwY+ZsCULU1lShIC8P9o5O8vzKqkqRuQ0NC8OF87GSIayoqETU6Chc7byKxMRE+Pv5Ye/ePbJuhIWFiaJkTW0dRtnaormlGfl5+RgzJkoc7pq6BgQEBuHj9R/KujF27Dh5Zmp6JqytzNHa0iprIv/PNTU4JER+l5ychKLiYnh4eEnus5xBmshIjB03TtbfgY7BObR9cXxMrfaW1rttTOFAzeqiP+oJet8mjdBIw4j0xUfyvYYDAzkIs972KUIldXVwKoS3snvfvw3rN1KhtrYGv33913j0sSdgYGiIttYWfPbpJwgPj5BI51PPvQAjIyNs2bgBfgGBInywbesWNNXXoq6+AYHBIYieNgOv//pX+NGPXsOpUyckTd/U2AgtLR3Y2dtJ9PW551+Cp5cX9u/dhfETJou+uhhLxocG/vPWm7ILDQ0Lh421Fd748x8ROXai7GKXLnsQ+np6OH3qpHD/UXjh6MF9KCktQ2FhkfDavvbTn+PMyWPw9PZFVlYWzp45DRcXF3kPKn6dPHEcz73wCuzt7USUYcy4CdfH5rWr4jhv+vRDXNXQlB18cUkJggKDRH/cx9cXJibGOHzkMAwNDJCXk4NXf/gaEi9eEPBEUHCowAz27dmFUfYOiIyMwvlzp2FoYAgDYxNs3bQB/oGBCA4Jx66vd2LFgythZm5+/f1vu7PdxQWSH+uSWb4X89NdNPUbl/aW1+wt/dmd8+tR3FT3KRmPMjdyHuklFSrn8x+DHK9D+g69cN8CRenCjcs8p4am9I0aDeXj7/hefbGMN0iddt/1NtefO26McuF33gIqFc6eOSNzdXBwKCwsLZCWclnEbXbt2iWRSl1tLUyKnorWxgY4ODpi/6FD4sCuXvOoOJv5BfkCEZs+bYbwxJ45c0qirw8/sgZF+TkiehAQHNYrsKESZct//u3PePLZ78HI0Bh1dbXYt3c3KisqZX0KDwuDu5cPrqSn4nTMCbi6eUiA5vSxQ9DQ1oGzqzvOnI4BIRELFy1G7JkYEKo3MXoaTp88DpWGJhIuXsDoqAhoamjD2y8AO3Z8BQ0NDZFUr6osR2tjPdIysyXaGxQUjMCAAKRfSYO/r69kSk+ePCnt0DcywYnjR5GWmgpPbx9x4lc+vAp6evo3BGv66ysDOrScjujd86WJlauqqlQvaEZGggPRwDWJ/Az1wWfSKSHOhApGDM/LJNkdfeoNMuk1aXKHosamaN94/lA38Dbu19jIcH6TRAq562CK2sTEDHp6Q2+322jWoE7lDkqd2uh2Fnpf1rVoqTRkgLW1toqoQG8tbkGLXrsm2EumT5heIEaGaQ5dPf1+MZ+DatgtT1JJCuXHP/y+RF5NTEzh4eGB8rJSrF77OA7s3wMnR2dJt9dWV6G4qBDOrm749a9+IRjViRMmSSrlYkI8Zs2ajajRY3DsyCFMip6Gzz/9GMFBQRg/KVoUtTy8fFBUmI+CvFyERkQhNydHdtghYWGCaf1k/Yey+6T8LCOgH7z7b7z4/dewaeMGjB8/Dj5+gSKZ29LcDHcPT3y+4TPk5uVjwvjxKCoqwPm4eEycMA5z5szHrh3b4BsYhMT4OIyfGA1nF2cUFRbCzcMTZaUl2LLpc7zw8vcF4sBxSulapoV2b98qk5WZuSX27t2ljrTu3wdjI2PMnTtPHOfRY8bh3f/8G9bWVvh659dwcHTCY489Dm9fPxzcv1fsGB4RpVadMTSQdpeXFsPE1BR1dQ04evggJk+dhs2ff4ZVq9fA0tLq7j/jbdyBkJD83Fy0t7XBwckJ+gYG4sxzvtDT07uNO93bU7lJqq2pUSOxrwEWVtay+eJ8S9iLYN00NWUzpa2jq8Ywa2pKNIZjieON8wsjKuxDvNbSyvom43V43o2iH7R79/hu5dxdQ/UhC+jqaMsi2NmhFvboxowPT0tu/65sm2AKGf1RqVBfWyuLP4nkmeXhMsN0Lje/I+bo5YT3j5+8XoSqRuur/3l/D3WFgRrvrxal6cb7X8dtako7OZYJXRopwi792bB7j8l3ob/RH+61X3urVIg9dw6XkxMREhYBC3MzHDx4QNZOChawhoL1HjNnzUFaWorMaVnZOVLHERwcIvaxtbPDpUtJcHZ2RV1ttTiDLU3NWPPYYwIDo/0am1oQGBh0Xe1RpcKJo0ew6fMNiIyKkgBK9LSZ2LTxMyxZslTUJ691dojUrY6unmTyHBwd0NHWDi0dHckONjbTF9DBkqXLkJ1xBWlXMuDq6ioS627u7lJfUlZWhtamBphbWMLA0Bil5WWYNGkKzp49jca6WvgHhuDgof2IiIhEgH8AcnJz4O3pgYaGRgm2EA5IpU0dHS11xDg8QtQs6dgT1hYQHHLLjfEADq0KBQUF+GrbF1i6/EEcPngAqamX4e7uiSnR0Xjzn3/HtOkz8MCiJUO8+1Zhx1fbkXI5GS6uroIhpO59R0e74BRr62pRXVkhjnR7ayvMrazFWLp6Bmhra0FmVhbc3dxExcLZ1UMm1ft1MJW8f99u+eiMwNGxpYQqw/bTZs6+r20b0CYqDfz9b3/G8gcfgqOjk2B5uEsSXeeGerQ2N8lUSVA7Uxx0cPSNTdFQVwdzCwtxpurruClR4cyZ01i4eAlMTEwkErjtyy+wbPkKOLm4DbjrGrCdNzmhsrJSFiUtTS2YmZuJk6Cvr49WFodxJ6ynJ5NrdWW5pGHkverrJaXT2NQkGw9XN3fZyMmmTlsbVRUVsLK2FtlaHiykUr8jYGJmjuysDDTU1Qo+iZuAbpwQFVjoyBNGQOlbYlQJvNfV0RXn/nKyuq/r6uujuqpK8FRciBiptbW1gY6uDjoJyNfVQ11tjTgwjDyrGwEUFuSr8VO2o1BXWyv9zNpmlCwgnCypTqbSUMl78KioqBCniNgmtoEbQDq2tEFjY5OMHWtrG2lrZsYVkdcNj4xSxwVVkPupN5hAelqKvIOTiwt2bt8u0ANeO7iw/p1+3evXUdns4IH9smExNDRGR3sbJkyahDf/8Tc4OrnixVdeHeL56e7bLHegMlttLdZ/+D7Ky8sRGhoqm6zNGz7B/AWL8e5778o8Nu+BhUhLTUFQcAjeeetfgr3+aP16SfWteGgl/v7XP8umhgsrHclZs+eIxPG9cGLozLLvbtmyCS+/+kOBqyRcOI/jx48Jhu6hVatl/SgtLcUTTz0zolSF2PaPPlgHY2MTrHjoYVmQf/M/v5RF2tPDA8WlpbLQR0+djtlz5g7RR7+72zAqRklrOtgcs8ePHRGcI2E/VAUkdjE3J0sgU6wdSEq4KHUBjLjdq/HY9w057+XkZEv+xM7BUSBMlFRl5E5bSxsZmRm4eCEOYeHhEnw4FXNSahe8fXz6LVy6Owve3tUM2jENbmNjLWsgD26UL1w4L1FG4k2Z7WJKnQGJwTjhHPMMYlB5y9zCSnwqbkwjIkdLLQYPOoTMBl65cgWWlpbQ0FShtqYOrq5uMs9zvs3OzpJ1y9LcXDazo+zs1LCDzk6RbGd9BwMO3ZkRFpNdSkqQtdvXL0ACL19u3YwXXnpV5p+sjCsyb3Bzyn5UXFwk61jM8aPyXuMmTBIlSWtbW3kGbXP5UpK8d1NTo0AgmD2MJVzN1Q3ePn4oKy2GubmFbMgJq2hpaYW5uZlsEg2NDEWRjAGSjvYOaGppii0rKyokWEM75WRnC5aW75xy6RImTom+G4cWEh4+E3McEVFjJapka2MLAyNDATIfPXJIKu9WPLxqiBcMFTZv3ogr6WkChHZydETMiWPQNzASPGNpaYks4HROuDuxs3dEe2uz7CpmzZkrOsT8WIwuzpm/AN4+vkPcvsEPCi4yJf9N827dslEmzrLyCjz51NP4atuXWLJshQCkR+yh0sAffv861qx5FM4urtj19Q4EBAbi3NmzUsTk5+uH+AvnJZ3u6uaGtuYmxJw9JxOXm5u7OENSUFRWBl19Azzx5NOCMd2/dzcuXUoW8PvDj6wdNodWnefse/Tkb3v+wMHGiIE4af0eva/pnQdWn8wJm5gn/oU7TDq5TOWrj77nd0dPbvw9HU0usHq63dHE7mcO3P6+z+F9uqMG1//W+3793fvmz+METkefzgqjherjepUrI4RqJgkt2QiYm3XBDu5Rx+bGZffXO7BwyTJZDDn2J0+JxplTMbiSkYEf/vi1+zb+B2OCuLg4wbFxI8CFhOk8ewdHbN36pWzkjYyMJTIyZep0HNq/F+MnTMC2L7+EkZGhQGWI325paxecWUhIKGLPnsLseQugrXWz/jyYVg3mHBXKykrx6foPUFhUhB/86Cewd3BAQ309Dh/cj8L8PASHR+DQ/n0SeX7iqWdhaKA/mBsP+zmMYsWcOI7333sHM2fPkXmoob4O//zHG5g2bRpaGQ0KCceeXTsxb8EC0by/Xw5hjzFUKjQ1NgkOPzxyNPLz8yUTw80ynQ06XMmJ8RJ4WrHyEZG7JiZ/ypQpGD9xyv1pv4py3PXYuOFTONg7YNykKdi+dYvMHqxv4Ab8UlISSkuKUVNTLRE5RjAZDFi8dJkUB923Q6VCYV4uPvroQxl7EydNQmdHJ87HnsWnn3yMH7/2U6Slp6KoqBhWFhaYM/+B23DA1fM/+2FNTZU48oIR7ZlWbzYfd8+93TCe3tZRX8MiLgYm6B/dmFntuqbrFqmXk2VecfP0Eo6ermD+9RsKg81VCewwI8/7fYPIpzcjpQqSiWEQydyc0LshOLruz3fqLTV/szsPCDngYnYx7hxcPTxlcE+fMRuJF+MxYUo0Ui4lIycrCw+voVMyOBqHwb2iCps3fQ4NTQ1EjR4nkZcNn30CKysreHtz16aCBiNOpFrq6MSVpx++zwAAIABJREFUtFSJfPEjvvTKq/hiyyYBKFta22DShPGYPG3mMDpNt3gjlUp2O1fSUlBQWCQ7Pe7Eli5bjoMHDkjE0tRETQE1Ig+VBn73+v9g1SNrZGf42afrER4RKYB2pkNXrnwYhw/sw6To6aivr0V1eSlOnYvDeEmXEwPajrzcXJSWlMDF1QXfe+Elcfb+8qf/B21tXZQWF+B/Xv8DRtnbD3H/uUtrEken5sPq5ZDe5J59ITDd8JeeS28SJ+uLoR6Ql7ALl9iNmexpTi98X889ujHoEkLuwl32mgh7OG77wTUOK7b5Lr/LTS5n5mDr5o1YsHgpSkpLxZl6eNVqSX/t2bULP/7pT0dW/+rzHufPn0dBQR7mzV8oi1pKcgKuXb2KLVu/xNPPPIMP318HPX19PP/iKzh57IhE8uMuXJAoT3trCzy9fJCdk4OoqCiJbGWkpyB6+mxoafYHExrCb6BSSbaFmwlGMp94+lnBo+fnZKO9sxPbv9wqhSFpl5MlovTSD34sGZqhXSvu7H2YOWGQoaqiDBqa2nji6edkPaGDy0V+/IRJaO9ox/lz5/DkM88NEzTq9ttOiETihVhYWtsiIf4ibB3s6BXJHOri6oaa6irEnjsDVxdXfLl1ixSwmpuaIjgs/PYfNkRXMKrM4lVm9IJCw6TyndHH5198CQ6OLtI3WEfAzTKLUAlfampuxvwFC+97RJ8RxWNHD0kkdfSYsRI15AauqqYGq1evkY3axk/WIzQyCpFRY+6sn/TgzYfI4H1v0xej3/V3Zifp8KqXuV4Blr6+XL/t67UefeN5vfH0w/RON7ntgA4tnZL0y5fg6OKK/Xv34PDhQ5IqWLP2UaSnpYqzMmP2nCGepFQ4fPggbG1tERAYLNHYTZ9/huqaGnz/Bz8UB5YDmx47Q9+XkpNRUFgAXS0NLFqyFMWlZVIBzrTuSy+/Cut+aCzulZmlyvyTjxB/MQGr164VPOr6jz7A0iXLMGHy5JFNc6TSwBt//RMuXyJo3RvOTs5SEe/o6Ag/P3+BnVyMi0VIWDjq6xtQX1ON5NQ0hIQEIz0tXao5GYEmltTdwwOLlixDHc9JTsKs2XNx5NB+tLd3YtbcuUPcf+786zLayqwE0/n1dXWCrWPksa6+TtIfZDTIy8tHQ0O9wCz8AwJ6dsVM7ROSwb+p8Y16iI+PEy5b9kFGrhh5E/ywrq5Eq7sxxsTx0YMmt2xvloLuN+GGjZOpte0olBYXIjc3V1JWvr7+wkDAg5FmtoH3TEm5DDu7UQI7YKaD70GcEyPjhPC0tjbLYkEcc7cPTieK45kUZ4NJnd25lYf+ytTUVHz04fuy0SI2a9WatVJIwWzCqtWrR0z/6u/N2XZu2sdNmChZgpzMK4KpPXToMB5/4kns37dXvvcTTz0t0Vh7e3thqaBzePbMKUyfORsN9Q3iNKSmpuFnP/uFZD/uSUSR3MYdHbLJHT1mDI4dOwoTY2Ns37YNM2bOwoJFi5GXl4v0tDRMnDQZero6Q//x7+SOXYW6paXFyM7KgqmJMZycXfGX//0jmlvbpAiF0SZjQyP4cIwPacDmThqsvoZOCDc8TDWfOX1G8L+kbmIBj5OTkwR4zp2JEcjQlo0boaGlhYkTJ+GRNY/dm/7Q76upEB9/ATVVFRg9biJ27/xK6hOeeuoZKTaKOXkchQWFEuBh8IypbPYZMrZcz3Tduc3u5kqm6dm3Cd8IDApCaXGx1BGcPHkC8x5YgL17dku9wNPPPS/+ykg7SL2VmnJZot9hEVHXMbW9hHvoQ5GZoL6+Dg4OjgKt+wbWvTcJAIDGxgYJ1plJNm7kHAM6tH2bSsA/owg9fJPDFdG54b50XDtkwZbCgu4Cpa6PwthwR3u7OAOC8dPQkHO7ifHvdyECU8Cc9An45iLDjsBO823g7JSiwNY2cXCI25S2a2lL9LyH6aL3ZN+LEYPYU7UwgE7P+ZIU6XUOI7YjyXlqam4ROipTMzOUlBRh7rwFqK4ow7Fjx8DUtqenl0T+T8ccF8dw5SNrBNudlBAvCyKd33f/8xYiokbDxdkZv/71rwR0TwgAqbDCwyMF4B4cEiZOc1ZGuvRtshjEx8XCzy9AOHF7OyOMcJC3kBs7Yv22bf4cpRUV4ozqaOvg5e//QPo6q2XJV3s+Lg4ZVzIEn21lY4PMzEzoaGlh3vz5iDsfC30DfXCinhI9Tb5lYkK8ONqOTs44uG+3VJZ6enrfxwXwDiZIlUo2CkyJXS8+YpT9/kULbu8teufuuq7saftNWAK6nLLuvsI5hilMvv89d8DIJcl5rrMDmhpa6nEvRWBdWYAR/h24kWW0ilOZFOBpa6mLmEZYu9m+8rIS+cakTDp2+CDsHBwkyKS6dg3GpubIy82WjS9xiiXFhbJBtndQ4z/vz6ESTu2WliaMsnfqqopXISAgUGBphBi0NDdJ4am+obFwZLMoVTC2vUQH7kfbu/lbtbS1oKHSQE1NjdBtkfebjC4xMSfR3NSMqDGjBWZ3L3Drg7aDSkPYBcivTq5yQjKXr1gpFF3WVtaCWc3LzYORoQGOHz8KaxtbGBsawMjEVGogWKjFImEOCvpWHNOsCeL4KCzIQ1lpKZYsv5EmctBtG6YTb9uh/SYmcJha1i/2kM/qD9rQuxt1//2bWMfhaunA970ZjnLgK+//GTcbojeDmPQB1fS8QO/z+1m87/+LSgsogPDBuneRlJiAJ596Siiptm76TEDz/oHBoMM7acoUnDx+FBMmTpboKCdrYq2CwyJl53pg/16MGmWPttZmYSEgPsrIxAQ5ObnyOxtrawQEhaDjaic2fLwepqYmePypZ2UXnXDxojitPdRfgNzjq21bkZWdJeIMRQV5KCkrxzWVBqZGT5W0IlONLHB5/qVXsH/PbnRe7URmRqZkKViMOMrGSnbhZA6pqKySCDE5B6uqavDJxx8hKCQEjz/xNIoL84TKJYLps/5kx0bId+q/GTebB4YSDjVcBuhvTPQdS/2Nof7G2/14397Y8L547eGy2XDcdyStGzd/P7WF1Zs4puq7AwzilPcApUYOXZo6C6TWVmTUkAeLYpmJ4OaagRLJaunpSQBF1AiHGzIz6O7Tt+7hZhfej3F3i5focmg3biBdZSSOHT8uNUmsM/Dy9IKBvi6aW9tFDIEFW/xGNDkzP1TZvBAXj2nTpkJPX09wsTyYDVdpasHO1kb4YxctXX5/4Jw3ee07cGgH3QuUExULfOssQIeVxY8O9vY4dvQI1qx9DIkXzkFLRxfWNnaIi4uVNCphL9HTZ0kKlVjNyopyePn4yeJCPJiorzQ0wsPDXRguWLzDSfrixQsiikC+v+kz5wrekdmFCVOmobAwH6djTuLBlauEjYDRC84y5C08cGAfbEfZITszA65ODsIOkZ2bBw93dyl8JHD/g/fX4dUf/AjxsWdF6IBMBuQkZKUrd+ERZCnQ0MTOHdtlYQkI8BcnnepkXl4+og6Tl5sjlfKMIH/7HNpvXXdTGqxYQLGAYoHhsYBKA5WV5fj3P9/A1KnT4e3rL0qR1ZWVsl6w2PSxJ57CpcQExMbFqRl+bK3h5x+A/MIi5GZnw9vHS3hr9+3dg+CQUJw/Hyv0je1trTA1M8XS5Q8pDu3wfD3lrooF7t4CxIzHx8UJqwNTX1c72+Hh6Ylz584JFmnCpMlSmKitowdHRwd5IPfl6akpQlXCStDMjIweXt6vd2wXkQbyCiYnJkFTi4U6KqEIIg2WGjN7TWAyp06eQEREBBoam4WkOnL0GOjrGyDhYhwcnVxgZ2cveLPaynIEhoRBT99AHOBFS5dJGighPg5WVrZCz0UxBDrRYWERePedtwTrtOaxxyWa3NzYKNylxKSTjogYKnU1rEruTyeYHIb3BIN5959MuYNiAcUCigUUC/S1gEpD1LmYTZwxe57UdJB39mpHhwRerKxtkXElDfr6eiIWxKJ6d3c3UStrbe8QTDCj5QJvqasV2fiiohKBFREuaWJqgqkzZisOrdLzFAuMaAt08asOCIjqhR1mwRaZHhycXHorDl5/zX6ZsrowniAurgw1VVXw9PGRYjSyhxDLKlHanizo9fN75RW78JIqgSxkZ5JLMFR4a79x9AH2q73xbpwpf7wqvIAUJVCc2RHdQ5XGKRZQLKBYYEALsNBXLWKkJ8XZ5OwuKSqEmZkZDI1N1Hhraxu1eEt7O/QNjSR6y/oXii9QypwBD/LKM4LLug3islmYytoOOskjaa1QIAcDdgnlBMUCA1uAfiErjq/ztA58Te8zuqOk3UpqLO65fR5RNQehFEbecaXdyMU3355FlbMVCygWUCygWOBGgtm+dQZ3W8Y2snDDikOr9HfFAooFFAsoFlAsoFhAsYBigW+1BRSH9lv9+ZTGKxZQLKBYQLGAYgHFAooFFAsoDq3SB/6PWKA/6jS++q1o4G4mEXszk90sXX+rNM9QPv9Wn/J2qWduRl/UN0U1slJO/0c6s/KaigUUC3wLLVBUXCzFV+QItrG1EW5b9dGXku/mL0c+WB7UA2CBFlXVjI2MpKi3ta0VHe0dItrzzfuqf9PY2ITSsjLBx7INN3JWq2FrVEij8M6N0rnqdhKTy9aqZdpvJdGrPp+MPSSkJmf6QOfX1NYIbRjtUl1TDWNjY2j1SNIPvNYoDu23cFAoTb49C5ABgBRW5GQ1NDAQ3tfyigoZ+FZW1jAy4uBXczaSD5GcsxxIxsYmKC0tld9TopgDkxKk6vnnmprAvquAjAVVFNDQ7Bb96GoiCdv5bEo9UjCBlaGlJaVyLysrSxjJRKQe5qRCYbUpn8l7kx+QJNhsp4WlhdxDXSSmJrGnAlnv5/N3Ghqa33DS2QZOQnp6eqKkRTWq2rpaNDY0yHPMzc1RVV0tbTI3M5MCgvKyclhaWnZNjNfQ2KUNXlNdI+exbZw8jY2MR1RRwO31DOVsxQKKBRQL3AMLdNU0/P63r8PaxhrNjQ2YPWc+3Dw8Zb2xsbFBW1urzLdkoGlpbhbFNDINkNucczsZb7hO5OVkiWqko7OrKKllZWXC0dFZira4DjU1NQrFI5UpnZydb3BYuQbu3bUTJWUV4rDOnDUbVl3iCeQmLywslGeUFBbCL8BfxDsM9PVhYGCIurpa8X3Ly8tEyS00LFyEfCoqKmXdU/PZFoEiFLymW3GzurpKVBvJgWtmaobSUgqD6MLM3Ex+T4YfFqGxUI0S2mQFqq6qxtatm/EwFfs6r0mRM9epgRC/ikN7D/qy8oj7a4G0tDRs/WILDI2M4OXlBXMzU5w4fgJt7W2wsbHFM89+D3T6WPHJHekHH6yDl6cP5sydg/f+8zb8g0Pg6emJxIQEoeWio+fh5QU7OwdUlJXAwtIKJSUloh4zcfKU6xOIiswDNXjrzX9BR0dbnMk1ax7Fhx++LztQewd7PPXMc+LNVkllaQcqqqqwd88emWyiRo/GmdMxUKk0MWXyFFxKThCqLksrG1Ebc3V1Q1V1FbQ0NWXHn5QYDzNzS/l97x0/JxZy6k6fOQtHDh0UGd4zp08LZRgnUmsLc5w9e1bEHziZjhs3DhcuxMPE2AhrH38SmhqaQiPGyejEyeNCxh0VES4OMeVaGSlQDsUCigUUCygWuIkFulT9fvmLn+Kll19F7NkzEuigk5aSmobw0GDk5+XB29cPtbW1yM7KFOdy8dJlQqNFRgEKGWjraIuUeX5uLiysrDF23DhcSU+X+f7ihQsICQ+XIEVlWRkaGpswfcZMcTxlPVBpCG3j1/+VHl68ZBlIUZmVkYHm5iZhMrCytsbxY0cl8DHKdhQsLc2wc+cu4aXV0dZEfn4+LK1tYWVlJZLidJ4fWb0Whw7sg7GJGby8PLHjq+0ICgqSoEdxcbFEgcMjInD4yBFZN6dMmoRjx0/A2MRE1tQdX30FU1NTWYudnJxhaWEhinEX4y/g9KlTePa57yHuwgUJPC1YuBAWlpa3VEFUHFplBH7nLXDx4kWcjz0nHLIcPKmXklBTWysDKCEhQZzK1JRLwq1XVVEu0raUj21urEdhTg78g4Ph7eOH06dPobK6WmQD5z/wgEQ6P/lwHcaMnwh3Dw/EHD+K2fMWiJBBNx1WVVUVPv7oQ5l4Nn72CZ565lkcOXIUIaGhyMrKwmOPP4mG+jrEnDiG0ePGo6OtTSK5Bw/sR2JiAvz9A+Ht44OLF86LuldhURFMjIwwdsJE2YV/sv4j2RkvWLQERYX5qKqsxJhx42+QVa6sVLchIjISR48clrbk5GRj/MRJMDYywaWEOJlcJ02dIaILq1atEQW0P/6/3+LFl14VpzkzPV0mKdK+kKOXQhL8f0BAMAKCg+691Op3vtcqL6hYQLHAd8YCXQ7t67/+JX702k+RcukSdu3aIZzfS5cux/59e8TBe+Ovf8ZvXv+9ZO74tx3bv4BfQDA0NDVRUloqkc/MjCuYOWMmOjqvYv36D0WJ0sfXF/PmL8CxIweRnp6OiPBwBIeG4R9//xt+/svf9JixMD8PBw8dxNpHH0dra4vQRVJW3UBfD6lp6fjFL3+NysoKWY/ycrLxg9d+jtMxJ3Du7ClRkqyqrsH776/DyocfFsnivLwcTJ8+U2AMRUUFSEtNQ9ToKNTW1WHZ8geRk3kF+/buxeLlD2Lv7l0IDgrGpUtJyMzMgKOTE7y9/WBpaSER2+PHj8HY2AitLS1Y/uDDIkFfXlEuUV9Lc3M8/sST8PTx64rS9g8/GIRDeyvZ1uGm+LkTGcLhbtOdDLH+AuUD40Hu5ElDf81Q2bPvfYbqvgO/cXx8PLZu2QwXV1dxPK92tCPm1ClJibz88itw9/SWwUPnkWmPLRs/RVVNrUwIvr6+yEhPk90rOfjOnz0DCwtzGBkawcrWFps3bkBoeCTmzl+IbVs2yQ45KDgUWpoakkqprKzE//7xD+IE+vj4iCLX3/76J9m5rl77KPwDglBRXoavtn2JZQ+uhJ6eLk7HxIiUZUN9A5iu8fDwlH9TKzz23GmJjFJtzM3TW+RuTUzNsHrNo5LCuXA+FsGhodDV0RPpSNJ30al+699vwtbWRpzkxYuX4mTMSdiNspOU1rXONiQkJKKuvhHLlq8QQYZjRw/DPyAQgUFBMkldiIsVLkKqzLi6e6ChoR6XL13ChIkTRbyB8/U38VYDf5uhPePbKjE92PmhPxx0b6nvbjzbvZ5b+pune//uTubxoe0ZN7/bQPPQQH+/V+1UnvOtt4BKA797/X8wYcJESbW7e3ji6OEDsgbo6OoK7WPCxXgEBwejtbUNzc3NAnVzc3ND5zWA61hjfR2MTE1hqG+AstJimFtaoba2Dvp6unB0dkFtTY1k2UJDQzHKzh7btm3FkiVLJYXPeZ3whX17dsPOzg779u+VjOEXWzYjIDBI1guuLdraOhIQ0aXggrYOSouLUZCfJw6oto6uRGbZ9vgLcbIOMbtYVFgANw8vkPeWfOipqamydpqamkFbWwuubu44c/qUOOH6hLSVlkjG1MZ2lKy5VNFMTEyUrKC1zShp56lTMQgKDBToBNftKVNnyDrk6+snAZf+jgEdWsp6FhQUwN3dXdSIcnJy4OTsJB51RkYG3FxdJRw81OS61dU1ol1/7WonHBwcYWdvP6j+3NrSKuFrYiDl6EV+P6gbDPFJXFqIGSkpLhEbsrOkpqZIJ+WHHOkH8Zx0ZHQkrdylDd5Po4mBIa7HzMLiG3/t7OiU1LuZmanwtBIbxEiilY21pMuH+0hJTZVBzFQGMUW6WlrQNzAUAYHDB/eL/F9yUqKkzu3tHfHeO2/Bzt4Bfv7+SEtLFVwTVbtU1yDnmZuboaGxEeMnTkZtVQWsbEahubkF27ZuxrSZs1FWWiLE05xQmD5imn/eAwskFZSbk4NLl5Ll+587cxprHnsCba2tSLx4ET5+/sjNzcGnn6xHUFAIAgIDEHc+ViaXKdHTxKmm6gt3701NzRg/cSLa2zsEv8SJLeVSMuob6hAROVpSVs58Vz19VFVW4cjhQ5g1Zw4O7t8PGxtrMGptYWEJCytL6GlpyOTi6uEtDjqj2BzboWERWLhwIXJz85CUeFGkD48cPAANLU1ERo3GhfPnER4ZKfAJRo9d3d0HxDgN17cmNoypOLaFkAoDQ0NxxJ2cHCVVN9Tz012/RxemjjCU1JQUwa1xDAWHhEiEgkdDQyNG2bHtQGVFhWyQTE1MUVNTJfPIlStX5F3NTE1RV1sHOwd7ibgwfUhIinr+6/nHXTe5vxsQqpObmytFJEw5cmGi7nt2drb8zOxCelqaKNXZ29vdBT/yUDdfJWOTcCQXFyfY2tqhoqJc+nH32sG1jhtS4gQdHNSqgCPyEBx/12amtwjLiGts1/rR0yf7bHpu2Pfc603ZTYzVm8+725e4Gcf3gL6GSjKBHe1tMDE1h4OTE/JzslHf0CAqkPSvTM3NUFNVjfqGeoGoeXh44erVDmhr6yI/P09gaQxgcD0lDtfbz1/GfltbCxoaGmSu6+zokDWCTjL9N0IICFsICAqWNY5rLzGwxMUyqHHgwF7Bt7q6ukvkFNfU8AYDIyOZU1m3QZVMc3ML2Ds4CnSAjivrMOztHaRdLHSzc3BEYUE+9PT0ce7cGdhYW8HbNwBWllbirLPNbAvXRwZaWKPC8UbMLUUf6LjSPzA1M0NeXh7au2AIlGMn1M/dwwtHDh1AYHAwRo2iP/jNPjKAQ6vCunfflmIaH28vFBWXipFpLC7YxH7o6WpjybIVsDCnIzNUnVCFr3fuQEZGOpydXeHl7S3pYX40qlpw50LgMx0s2Uno6cl/E19YWV6OvPw8iSypi2ks74nT1O9wUFHitAnbt27GlYwMhIVHwsDQAFkZmfDx9RGH6F44dHc8r6k08K9//A1Ll62QTQU7GDscF8yW1hZw89AdlWOnLy7Ih629o0TvWKnIlAal84jVIYZz/oJFMDUxFqzQxg2fYtXqtXBwImj96h03cTAXsiCKVZ2sDqVzyl0vB5S2jg4qysvFKaBTef7cGfj4+qGllRsiExnIxMYSkE6YQXtHO65dvSbvT1tw4EmVqgooyM+X3fX0mbMFekCMLSeIzqudMtFwkWRfbWvvQEtLswxQ7pqtra1kMBNwfyUtBe6ePlIIpqVF59pOoqvsx+pqVMg7cD6ls2NpZSn4Vh50LKjwoqOnD0NDfUkX0TnX0dOTCY7nM51TX88duLbsoumE8N3oEPE78n05AXJi5TjneU5OTrIBoWPNXTIfzjbwvVMuJ4tTzR08FWO4CRi6OWAwX1Z9DhVtDh3YLxMlnXQWsBkaGaK0tEKki2fPnQcnR6f70rabOYH1dfVSVMfx9PmGz5CanIiw0WMwefIUfPbJesyYNUcwZA8++BCsbGywZfMmWSxefOkVfPXFRmjp6qOuvkEWR09vXxzcvxf/8/rvsGnDpwKnefmVH8i3ZXEJ+9qwHCqVRJp2fb1TClLWPvoYLC2tEBNzUrB07BvGhoZITk7GqFG2WLhoKfT09e57kIG2YATs0IG9yC8qhZG+LsaNn4B//fMNrHpkNaLGjJc2/uqXP4P+fxdnbkZDQ8NGTP/p/S1ZiFpeWqouVlWpJNNEJyN66rQRh21PvBiPmNOnMG/uXLi4eiApKQGGBoYyr3BOJRyKqer5DyxQF7ze70OlQnpKCg4dOojx48cjKCRUfKEvtmySeTIyKooTL3Kyc0RC3J6byIGc2t4qlN2bkOs7z+tBI9mfdG1UJEnQSyWyxy69/t79u96kA13X0PmkUE+Pr9FVVMw1sK6mRgJuzLppa2lfV6Xk/XolfLiJNjIyhlZ3vUSPwmSvjVTXj/xTVWWF+ABcY9Wvd12RcsCoR+93vSHpdE3WL85nWlr9B8IGjNCSEiI/N0fwcmGRo5Fw8SK2bN4If39/rHx4Nd781z+xdNkyeHl5D+GAV0mn4S4/ODhEUqU7tn8pC3L0tBkSbUpOShLPXlNDS7CANVUVMnk/tGoNThw/JjuS+toaPPXcC3DjQjxQRxuOwaPSQEFeLt7425/h7OiIsKgx4tQeOXxQBuzM2XOhMVDZ3nC0a7D3/G/k7Y9/+B0eWb1GUuZbt2xESGgYTsWclPSAmYmxOHHEg86dvwDXOtuxc9de5GRnYdasWZI+YBSpsqoK1ja2ePzJp2VQnIo5jvy8fNnpzZ47f9gd2kG9bhfGqYNMA3dR5NTNKHDbToRKhZamJtlV33Hqvld2lBWzjOLduWLYjVZramqSiJswOwCCp+VGgY761avXBCJxX8YYgIryCuzZtQMLly7HubNnpH1jxoyTwoO//eV/sXDREikGHCkH57W33vwncK1ToCqurq44vG8XHlrzhNhw7949kt7bsOEzmJsYw93TU2x8MT4eY0aPQXNTHSpr6/HMsy8gPu4ssnNyUZCXhzlz5+LQwUNStMGIOyWUx4wbh7DwiGH7Ntz8lJWW4eOPP8RTz3xPilz27v4aB/bvw9LlD6K2uhLHjx6VSBIhNkw3joSD41Q2bq1t4gRGT52OuPPn4OriIusc07Y/+/H3YT3KDkuXLYefrz80RtpkrdJAcVEh3vvPv7Fi5SPYu3s3osZESWaFkKaRdHDTycJc4kQvJSdj5cOrsHTxA/jBj36CadNnyrhlIRCzQMwgubt7DqE/cYeWUKkQc+K41Bcwer/ioVUwNNAXXOe2L7Zg8pRoJCUnSR0C5+yZs+cI1GzIj25qr+EI/PR3b/6u77N6sgA3ebu+fx/o/CE3kvqGt3ZoVSqkpabiVEwMxk2YAD0dXeTkZEmBDdOfnAQ2bfwcKx58CO7uHkPYAVXYvHmjgIEDAgJhYKCPr3d8BWtrawljGxoZS8q4O1qU+1/wcl1dPZrqa/Hs914U3Ah3UMSVjB09BtPFaRqq6PFtfAlxaPOw9YtNGD1mrICeVz78iKSVMzMysOKhh2FkaHAbN7zHp6o08Pvf/lp7yHE8AAAgAElEQVQqLRmh3bn9S8GVHj1yRHbUj6xejX27diB6+kzU/BePWlVeijPn4yXKVFhYIM5USspl2QEy0v7c8y/IC/zjjb+gpbUVVeXl+OOf/iqQhvvyffqaszuVdCd9pfe1MiGwv91mn+tvIrnTT94dCbjdNtz0ed3pwl6YTXkGo+v3F2dILPTOr7YLwwQxwkkJCVi6fAVOHD+KsePGIygo+I4lie/U/Le6jmluRrzHT5iIhItx8PcLwJ6d2/Do0y8I3OP0qZMyvvbt34fvfY9OaxzOx8ViwYJF2PnVl5JqtLazx6Ily3Hx/Dlo6+khJzML5WUliBw9Fs0cW5UViD17Fu+8/+GwRrvo+BFyQBYME2MTTJwcjdycLJmft2zaCHtHB1zt6ISmCpi/aDGsrPvyXg6HhQe+J4dnfkE+vv5qOyZNiRa8uBrOY4jg0AhUlpchLT0VDg5OEjlc+9gT0NHWGvjG9/QMlcA7Ys+cgo+/v8zLLc1NMDM3x6w5c+V7jKSD2anMK+lITk6SbBALXx9YsFCyWsmJCcKgEuAfgNbmRkyZPqsL5nZ/36Dxv9Cu/Xt3ITsrC89870VZr9nfCbeiA8uN/cYNn0idw8w5DFANbYSKVI2EqJGO0cnZRbKJqgHm9Na2NoEEML0/0MHiYGa/uyXbZYNaVibsNwxgDOYgpVhtbY06gjvIawZz3zs5Z0DIwdv//ieKS0oweXI0amuqJCVga2MrVEWXLyUJrmLWnHldfJq3uYDfYvGk8+fgYA8PT2/k5eZix1dfQgWVpCMqykvRefWaOEzc+dHprqmuEgeCFYPETBL7qK2pibnzH4DbfdztMbJ16uRx5OcXwI0YQxWEzoIYFUIOdHVGMuWRCu+++7ZEvl1c3cRtKS4sQHsXRm/ihIlISriIgOBgNNY3oKGuBinpGQgIDERWZqbgTYkTJt6TBVmswiQ05OzpGEnrXYg9AwsrG4wZO+72nb876e2DuIapmdKSEmEq4L8Jr2FlaUVlBbKzcyTSRxgCi7QIQwgLJyUKJEVPDltjE1OBDNBWjF6eOHFC8He0A/HITOEzZc8JvZuDltd3dHYItID4o/4cYeKPampqBRebk50pUTlOJMyUEP5Dp7I76tTc0iwRdHs7Ozi7uAjdGCEMvr4+EuUjDQvhIMSZkpe3+xDqsrw8+VZDOy0PwvB3cQq/GYvhuHkifRnfjfNCXk4uvHx8MHv2nBGFV0+/cgWfrP8QtjY2stF1sHdA7JmTmDlvkUCSLiUlScT78KFDMCCFjr29wHYmTJiAnOxswX1zY8l+yO80esw4wb4lJSbg+RdfkQwQad/q6usQNWYc3N3ch2l8qSRytXfPLlkQAwODJCVLTDcrmc3NLKSPMVvGBXJy9DRZ9G57o3cXfeNmlxJ7zoJKUhGNHT9eNuEZV66Iw2JkYip4vri4WLS3tcPD0/MbzCHD0KQ7uiWLbJIT4mFhZYWUy5cFTkXc46y586Xgc6Qc9AwYlGLGcvTYcTh58qS0k4GwF19+RQqLWOdQXVWFsIgITJg0ZQTA8VRCm8h1jL7GoiXLBOfOgBSP8MjR+OyTj2QMMoPJzZzmUEbxVRrCyLNl0+cICYuQ2punn3te5gA6jn5+6hoPYu7dPdyRmpIqcwX7MXGyhF2WV1TCy9ND1gquOXX19RJs4XrCTRwzWIQxcd7kuOQaw4wFYaSE2PHeDDjVVldLppUQStaeqNf1JhQU5MPejtj9UtTU1SEkJEz+lpSUCEdHRwl8kg3Bxtpa1tCgwCDxIYm7DQoOEbjbUB4DQg5IQE8cpK6ergB4uSOkKgWxEex8jChcV6UYuqbJxKipKbs0RiuIC6PDQAPxv/mBuiNDbB9xiaRRMjYxlr8zckAHgdVw2jfBWwxda29+J7aSGEpWDxLPe7VTXQXIXTQXnZF+0O7ExzHVTLxTfX2dfHum1LkDJPaUfyOWi7tC4i2J3aPT1tjQKN+Jg484Z0ba6TRxkeD13ElyR8g0zkg5WNzFlKmZhSVSLydh8ZLlaGpqwPnYWKEm4Q7Z1s4OZ0+dgrOzExYtXSHvlBAfB3sHB9lJkyKLk7K2lpaQXpMRgbhi8grSIeZADwwJE5xueUmROMN2jk7i6AvOmtmHXrtwdnVyBxKrumT5ConmXYMGdFnpWlaKF19+FSy8y8xIFxjHxYQEwQyTAoyp68vJyQiPjIKLs5N6AmxuRsfVq5g8eaqkptPTUoQCjJvTQwf3CfbXy9tnRDgeg+0XHR2dkgrk4sJNAbHLhETwYGaH32KkHDmM8MSeQ1hEpPQZOoBsKxccLpwcQ3wRzmHNTc0wMjYSPKQaQgIQf8v5WIjLDQxkU0KeSvYj4tZ4HWEzTJFzLuSGbLgOjntiwTkGiOnmXMF1ghkb0gmxHYwW07HlBm+kbJQ4pphK5jzFKmwu2rQVU8d8F7aThZ/8LpYWlsIjPRKPq9eAspIiGBgZi7MYH3sWnr5+Mo90w4Puf7tV4hwd2LcHejo6IiZgaGyK/JwsCQAwcNXc0iq1B22tLZgyY7Y4QCPhYAST0WNHJ2d4enpJQIZrOkUOGPQ4eeI4mhsa4BsQCEdHJxmfQ3aoNHAp8SLiz5/D8odX45//eAO+Pj4oKy+XcWVqYoaKynLhB6d/kZObg2udHXD38kFhQQH8/fxwOTUNZiZGst6yuGrc+ImIv3hRmHUIASLn+YsvvizrANec6poaYQRa/uBDKC0ukiABOWYryorFOSZFJIvYzE3NkJ6eJgWThLdww01RoMbmRhHb4fzLzIyTi4tk+C3MzWDO+oaGevF94s6fFzgUcfVDWUMzoEM7ZB9HuZFigW+BBQiFoBDCwYMH8N6692FpaY0NH78vzqiLowPsXDwkrctqy0mTp0iRYklJkWDMffwCUVJUKHQjrDI/fPAAXvvpzxFz8oRUlTJVZWtjBR9ff4SGhiMtPR3MgNjaWOOlV34oi2ls7FksXrr8BggGU0BHDuxB2pVMLFy8BBfOnkZi8iWYmJkjespkTJs5R5yG//z7TfzgtZ/i66++FIqwkzExXRtQQ2FQIM79/Xf/I86qsaE+omfMkTTrhx9+IFWuP3rtZygpKpDdeHjUmKGdnL8F3/5eNvGa5JuGKqN1L1uuPGvEWaBXoZHU0/Q0cGT1L/Z5Hup/qon+1T+q29kDZuoughoJhlZpSFBGXYvQq+KqG1LW8/dhYFRSaSA5MR6J8Rfw0COP4u9v/EU2q9HR0yTAR5gPs6GLFy/Dunf/I0E9Q2NjKQqsr61DZ0ebBC4KC4skiLJu3bvYuGkL/vKn/0/WgLDQMBw5dgwvvvCSXEfHkg7ttq1fYMWDKyU4+Mff/06cUW9vbzg6O6O9oxPpaekSnWXE+Ac/+KHUMzGKvfqxJ7DunbdlY02Y4ulTMbJuhoWFobqmFlOjo/Hee+9g3LjxIkLEQOjax59S2/VOYH799A/FoR0Jg0Zpw4ixADMDGz75WLBQZeVlePTxJ3Fg9w6JvHr5+OHY8WOSjrmcnISZc+YJTpu74fLyUgSSf1ZLW/j21FRc8Vi0eAmSkpOF94+pmjOnTkoKk2nYCZOihVmBEbpZcx8QYurDBw/iiaefVUMCuiJr586dw5dbNgkvICN1DrY2MDQxlQLNh1auQkh4pDAcrHvvHXFKyT5wcP8+KaqcPmuWVPhXlBbDzd0Djc2tiI87j9aWZqEO8/L1x66vd8DPLxCTpkwRh5ZwCv/A4G/I+I6Yj6Q0RLGAYoH+LXCfinGG5HPcTQ3DkDRghN1EpYGM9FTs3L4Vru5eyC8owKRJk3Ah9qxALil9W1paLEEVOt1cR5qbGgVre+jwIXFQyYlOmJmHpzt0tDShoakNTS1tdHa0Y9KUqVKoN2PGDCkgDQwJFYd5/Yfvw9XFFb5+vsi4ko7iklJMmjhJlCXp0HLtImTn+PGjsLa0QGBwmAgzMAvI+zGDS2gGmQiY7SNTD6lUIyIisH3bNpiZmkjxM/HHq9c+dsOm5m6/gOLQ3q0Fleu/UxZgujc+Pg4uLm7CxkAxA1ZmE7fEKKz1qFEICAyW9CTxsN047uzMK7AdZS8cgUz9E1pCmcLYc2dhaWWN8PDILgnDTugb6KMwLxfjJ0fLRNTR3i58sXGxZwVnraurj7QUtaY16XgIGSAnIHmMWc2vraGCb0CwwDVYYEScOLFOFEPw9QsQyMf5c2cFo8tnnzp+DHb2dhLJZaqJDjip7/QN9DBuwhTUVleJs802JCbES8qehNkjAev4nepcyssoFlAsoFjgNizAwEZGRqY4h6wnYqCF0AGmz1gfQbpIriHMCJLLnDSQVJosLy+TWLiak9YYuro6Aiugw0qYDYMWzNgRF0s4AjHj5GlnpJSBEEKHKBGfevkSRtk7wsePCl0qeRbpBnnQ8Q0LDUdoRITAQwmhrKqq7oE3sBaDMFDWdPA6QhOoL0CqQWZCuT4NNc5bcWhvo3Mpp373LcCkEh1F8rsSS0cskBYHZXOz7H5NqGpCMQiV6oYIJicQ4pjI50c8K51B7mi5O9XT1RMnlry9xBPz/lRbobPKSYL/YwEagfWBQSFSMZqbnQUvH185h7thTmjkfuVOl1hlNUZSUyLBnKx4ENuUk5kBD29v4dkkvpIRXWLduWsmtqm5pQnaWjpdnLpXu4oB1Ak/TjrcqesbGo4ozOl3v9cpb6hYQLGAYoGbWaA3MPcGotk+DDO92WYGA+btAnl8IzKuvpZiCLnZ2cIV3x8em1A7Roe7GRLUrb/Vc3u3vftdhxYWozi0yihSLDBYC9wynadGRN4pLvI6vqwbT3YHGEshzO6aUgbCod3sXYaSOmywdlXOUyygWECxgGKBwVngbmghe/zIQYoZCc75JhjX3hjoHgrHrgfcJ+iL4tAOrgspZykWUCygWECxgGIBxQKKBe6LBUhPSEhcWUkxNDQ1RVqdDE6kbuNBUQeeQ8YT+pNM9/PfkuHT1ERNdaUULbe2d3bJ4Gqp1Sc7OoRNihk6ZiT5O7KXkBmG4ZXOTl6vBZWGSrKD/B2zhQcP7pfiZqr/lZcUw9HFTX2ulrbwOJPNgFlKisLw/mQ14s11tHW67jH0ZlQc2qG3qXJHxQKKBRQLKBZQLKBYQLHAkFiAdJLnY88KTzi5bgkpY5HwggWLcSEuVuBxY8aNx+kTx1FbXye0YqSYtLEdhbjYc1IQfCkpEWmXk6ChpQP/wCAR38jKuCK8+GRLyM64InRqlGEn1SgxtpmZVwR+x3oRE3MLKYIuL68QDttf/vynsLWzx9jRUdDU1ICllQ3OnTkNewdHxJw8jqio0cKvTkfZzc0DZ86cFqjdxEmThSWBTAtDLXGsOLRD0t2Um3xnLHArIsH+qEV6FLm64Uy9NKtvScvUpbzVn+EEddAHW9Sj692FUeqr2X2zD9CDj+rTvsF8sCGiUhnMo5RzFAsoFlAsoFigPwuocOFCnDimUWPGIvFinNQ+sLiKdRHHThwXyscXXvq+KHdaWlsL7zuLyUi5RceWywm5lFnk1dDcAnc3N1haWAgrgbGpmYgvsAZkwZIVuHgxDmfIs+7iipLiIkyYOAkpKZfkmY6OziLkExQSit//9jeInjpVVNMc7O1gbmUtXMOjo6LQ2NQiCqEuLq7C15vMwmYDA+FCb29vQ1tbB+Y+sOAGYZ+h+PaKQzsUVlTu8R2xgErUlkgmTT8wNDQMFZWVyMnJgYO9PcaOn6iWY+zl9FLmk6pvFFDQ0dKCm6c3qivLhTCcrAFyfEODW4Xc3GzEX4hHR0c7pkRPFZlnElUzzTN9xkwYm1C28jrAnprtVlbWoqhTVV4GD28f5OVki4Kbto6uuk39PIdSmGWlpbBzcBTZamdnF6EV4/NcXFxkl3wq5qRQqIwZO1aEUg4dPIix4yeIAozCdPAd6drKaygWUCzwLbWAClROvZyciIdXrcaB/Xvg5e0HKwszfL1zByxtRsm8TjrIuLOnYO/kLNCEo8eOQVdLE1OmThWVSgszM2RcSYOGjj4C/HyF3jE7MwtzFixGaXGhOJyj7B2Em7y+vgGt7e1SwDxlcrSI71BIaffu3fjPu+9LUfLvXv81Vq9Zgy+/+AJ2o2zh7ecvHOYnThyHh4c7ysvK4ePrK6I9O3fukLVmzpx5+MGrL+GRNY9i1uzZQy60oji039IurjR7GCyg0sAvf/4T0bbmrjbA3x9v/O2viJ42HdmZGZgwcTKCQ0ORnZUp9CZ6egb4za9/gTf+8aZQcuVkXhGGADqzY8dNFG5a7l5nzZ13g1oT1X3Wv/8fkZR2cfMU2eYCKrsEBErFKN1YUnGR+aAgP1ewUuveexc/+8WvBD/FCUffwFDwSQ+ufASFhQVIT01B5OgxsuvuOVQaKMjNxrYvNmHR8ofw9ttv4fnnXxThCL+AQFEt47MvXbokO3ymhqKioiStRQf3wZWrRApUORQLKBZQLKBY4P5ZgJK0O7d/IesEoQARUWOgq6Mta0R+YZEw4yxctBhpKcmwsrYVui4qgomTGxsrawsV2d55+21MmDwZ/n6+sk6lpqbi8qVkET8grRajtV9t2wpNlUp+vpySKtHbqdNn4OiRw0Ix+fSzz4shPvlkPWbMmClqadZWlrImHTywFxGRY0QpkPRebS3N0FBpws3TU2ARYeERePftNzFn/kK1bPwQZwEVh/b+9VHlySPNAioN/PY3v4KdvYM4tePHjcVPfvKaEEITVzR37gNIuBiPhsYGzJg5WyRq33v3bTz2+JMiE0hde6Z0qMrl4emFPbt3CW7o5Vd/KHgiOo1qeixgw8cfoK6uBs6unmjraBe1FSdnV5SXFiE0LELA9SkpKZg3/wFYmJtj86ZNWPnIajQ11OPI4UNCBxYaGiptjbtwAfv27sGKBx/CAw8s7LKqWomnqCAXf//rn+Hi7oW4uPP4wx/+P7z99r9l50wpx9raalyMvyi0LGPHjUdQUDDSUi+jsrISk6dM7aEEG2mfSmmPYgHFAooF/u9YgLjZVsGeMovWS1dNHEcGIwz0DSSiqlY1U9NPcl6n7Lqurh40NDVQV1srCl2kc+R5LP4iVSNhAXQ4iZfl+cwO5uZki5z46DHjJJO4++sdmE5ZYkIYQD7aNrlPR3uHrG1a2looLy+X+1/PLarU8vZGhsLdnp6aiqT/yvkuWrIc+vp6Q/75BnZo+2Lw2IRujN9wK3v0fva3WSayr516cJdDy8F2d72jF6bzVt93qOg4emNVh3iXdsd2UGngV7/4KUJCQoVk2snBEW+9/W+RATx54hiWLX9IFLyonsJJhXimP//vH/Hoo0/A1MwM+/Z8LQOaqikTp0wVYP3pmJNY/tDDMDYyQmVFpQgcsOrz0w/fE6xTaMRomUi2b/tSHEhikCKiokTQgVy0DU1NIrG7ZdNGUR1j5SgVyJISLsLR0QHaunowM7cQ1TBe7+TkiOrqaplU9PQNUJCXhY2ffYrZ8xfiow8/wKvf/yE+WPee6GgzTVWQn4eOjk6JBNOJ19HTE1GGeQ8sgL9/QB+OwTu27L25sO98Mdzz01C9VX+47b4Y6RvGS9eDu6nZekmfyl/u9Xjqj8dyINq4obLd3dznZnPQ/bbn3byTcu132AJ9+Wj5qr0lebsnjR4R4V5yvX35a3ubqb97QDjP6awSitDe0S7rmbmZ+Q3O9A1ywD3SwL2f3+MwSlsp2MB7MUgzHMeADi35Memdk4qBcmn0silbplJpiDoRwcdDqcXb85IqFdrb2tS7Bk1NwWz0P1F3fYzejtZIWshUKrEZpeC0u+gq2tta5edb1R8Nx8e+1T1J7cFKRe6mZLelpS3EyjzUkcXuRZRYzbtwxHsWC5XY5BoFCHrf/16/+A3PU2Hvnq9xJT1ddq8hoWHS70aPHosrV9KlLzJ1w+8p4gZamoiJOYng4BBcvXYVGWmpcHX1EP1tFw9PuLi6yzuy/9bUVGHfnl14aNVaXLvaieTEizA1NYOzqzuamhoFtxsQECQUKsQrBQeHCqSAY472J7bXx9cPOrp6yMvOgL6BEVJTL0mUOGrMOHGSWf3K65lCsndwgLWVDepra5CWliKyvIwWR0RE4qvt21BVWQFvbx8EBAaJFCJpXTIzM2RXXlJSAk9PT8ycMwe6xOd+G46u+YhN1dVTt5lCFt0/31WfHcb3F6W4zk5whJFyh3homR90OD90a91f7dG9p2Qxoy09kwdx0zKRcJ7p6BHduGfv+99NIJ/LgzRBxHFzeuDv2K9kCe6Zm+9i3hiGb8C5jmOZYic3kMN32Z1jj5s9WeO+gU8fhgbdzi27vrm0q7ufiO9ACicGJ7qLRwfJN3o7z77bc29Yq7v7eFcxbc873O1Dhur6fmzZe1xK/9boWhOHqX/3/r435YRVzwE9h6zRA7Sn73tcX+QH6D9dwa9b+QG9+2eP79DFact2DqZ9d/AJb+HQqhv96foPkJqWjvHjxkGlqY0Tx4/B0tIC7m6uiItPhI+3p0Su6MUPaMBBN1CF3bu/xuHDh2BlaYXxEyYiKFgt9WluboHm5iZRbiIXGhcESre1tLaIE0YZz4KCfMEI8nwLC0vhZ7s/hwqNTY0Sqk9LTcP06dNFg/nggf1SOTh1+nS16tR9Ptra27F39y5s2bwZnl6emDSJWNEw4ZLjosToI23N6GRu5hUEhIZL+sPExERoN+jo1dbVoa21TSKI3OjQ9mbmZhItpHKWiamJ/J3pkaqKCnGyvLx85FuyYpILC//f1Ngk0q3GxsYi83fPjxsmD5lduwZf18TWvbD1sA70msz6m3i6HHjao7AgFy5uHv3cr9e9eyaCrgmp5zl9NhI9z+pqX9d5/BZ0VilzSOqWbmfnuuKCzMA3mrV7Yupr75G2iN+kM5B3Mf5CnMwXxP4GBQTAytYWBw8ehquLkzqybWZ2z7vSgA9UqVBZUYE33virYM58fHxgYWmJvLx8REZGYu/u3QgJCcaESVME6sL3TLp0CaMjI5GYmCCykctXPIQ3/vonme8oZ8kijyefegreIl08zIdKJRmJjZ9vEFnoVasekf69d/fXOHf2DMaNHYtxE6dg69bNGD9+IgIDA4e5Qbd3+4MHDuDkyeNSaf3o40/CxsZWbPjBunfgHxAk2PSysnIp0lRDhu7DfNTPK9HJTk1NQWNjA4JDwoR6KSs7CwEBgSKP3dzSKlkc4t/9g4KHvPDm9qzc62yVSqBSTHuzIJVBlISLF2QNJEyLQYOW5maEhkcMOZ3Tnba5trZW5hYHBweBkXFWvpKehvy8PIwdN0E2ngV5ubCzt5es2FAfXBMvX05GXm6eBFc4joxNjNWP6RV0pd2oNMmABmEDNqNGiV/0jaNXEJeFzIaGBlLU3H0wMJKdnYW01BQYG5tItlDt23VlfvgNK6uEqYCUYOoNa9fVvdrDaG5+bi78AgJ67k24gaOTkxQ2jxplrw5S3sxBv0NDDhihJWi4tbkJhfk5mDpzHs6ejkFNba0UofgHBKChoRFz5s0f4gVDhc2bPhd+tOCQUNEnPkZAcmcnJk+eIpEk6hnrMJrR3g5XVzcUFxcJXmTmrDmIiTmB2poaVFVW4sGHV4njNHTO9u1Zmo4fF6vUtFQUFxVBR1sLWZkZwgv3wMIlIwajSEeb+NHnX3hJNgRJiYlwcyNRcicSEhhNNMXoMWOQlZ6G2oYmKYyKnjpNFlJicE4cOyKLW1BwiFxPrE9E5GjBy1CedfzESZJy5+Dk4KOm9OToqYI99fH1l6hUYWEh0tJSQQ3oWbPndg20Ydr13t5n/FadzU1eN47qW9XwO2ws9cO//upLzFu4WIr3KPXLSDqL204cO4S1jz8NuxHK2MDefe7sWRQVFWDWrLnIy8sVK6SlXMbZc2dhamKCwKBgVFRUICJqtBCpc2GIPR8LaytrYabYt3cXyK0+fsIEeHl6IT31MmbMmX9PNst19fWoKC/HpcR4ODm7ICA4TOa54qICFOXlwMs/EDt3foVZs+chgkUgI+jg5i/ufKzMVWT1uHb1GnZ/vRNXMq4gJDREnZlJT0dRcREWLFx0T+w5GPOUlZXhQtx55OfnSZENNw98l/kPLISrmxvi486LE0Zp7MeeeLIr0n+/51GV1Bh8+cVmCZI8/uTTKCkuRMyxo6hrqJcNRFxcnKzTk6dES4bqfq3ZPd9ApSEQsPT0VJiamGLJ8gclW3bq5AnExZ7FihUPorq2Dlu3foFnnnseLs7Og/l8t3VOU1MzPvrgXSm4amtthompudiqrrZGuGRZFMZNAouyOAZ1DU2RnJSA8RMmQU9PBy0trcJWw2wfC8f4c25eHszNzaXIi/2FG7bujA7ZDdZ/9D6sbWzFQXd0dJKMIh1lZvRY15GYcFE2UxGRUYiMjEJychKaGhsFokYJeM4JXH9iTp7E3HnzUV9XK87vW//+l3ocMfvb2SnBPl9fP/Hfhupb39qhVamQnZmJ8+djMWbsOInIfbFlEyZOmoK9e3ZhwcLF2LjhM6xZ+6hwlg1Vo+jyb968EXV1dQgPj0BbWys2b/wcFpZW8PDwgBZ3yhoaam37jnaUFBWJY93c3IjnX3gZW7/YLIOdGMIZ06cjevr1D3ZbvWkITmYakc5h5pV0TJk6DRs++wQB/gGy+1+y/CEYGw39ru6Omq3SwOu//hVeePEl2f0LpKS5SU3krKUFD3d3cTqZzs7IypZt2fiJE1BbWwc9XR2YGhvhKjTE+SXVFScA8tXx99a2dqhvqEN1VbVQYDGaw8Hg7OwsWFBdXV1hFSCV1OXLl+Ht44MHHlgAb1+/O4Q3dMNQGD3tSsndkOIYRMrkjox4Hy8aCpjNrTCF3Vit3mmm7mhyz+69z079bqApt2FKTujbt27B0gdXIj83R7JIJO/W09PHzh3bZZ5SRyzv96Le/0txIS8oyMO8eQtQUlIsThad148+WIely5Zj25dbYWlphZmzZsu7ccE/c/vk5xUAABTJSURBVOYUCvLzKbguUd2S0jJxbsPCwhF37gxmzJ4nkJjhPqhSFHv2jCxwXBeYns/OysDF+HjJrBkZGePAgX3CRxk+whxapoqJgV/72OOyec5ITxV8OXHudBr0DQxQXFiI6TNnw8yMhTgj42CQhBnKr7Z/KbAoBgJSLiVLMGHajJnYvXM70lJTxQl55fs/km9wv/s+N9kffbgORoZGAqvhmKQqFYM9dHK9fHwli1lSlI/FS5cjPCLqvreZ/WPvrh0SzCHUZ/S4iZL14oZix/atCAuLkHVr3749EoBxdaUPNLQHHdqPP3wPRsbG4iS6uXvK+kyfIiQsTD4rN++UXCejTWFJqVBuRUVGIjkpESmpaVi8ZInAyOi0Er+am5srzioDglyHp06b3hMpraquwRebPsdDq1bD2NhI1uw9u3YgMzMTQYGBSL6cIus6s7UMNrLeglmBhsZGmBkby9h3dveWgCN9Hx8fb9mwOzo54vLlVCxbvhwXLlxAM883N4O2ti4effzxO1znv2nrmzu0XYvVT3/8fZSVlmH6zJkSkftiyxY8/ez3cHD/PsSdPw9LS3M8+fSzQro7dINGhV27dgr3Z0hYhBThfP7ZJzJZrln7GK6kpaLj6lVJSXPQ0iniAG9qrMfaRx9HUvIlXEpOhIGhMdY++hhG2dkNmcFuq7tKeL4Sv/jZT6QakKnPxqYmJCYkwN/fH/MXLBwxqRUO3r//7S9ir+zsbBgZGaGmphp5ubkCkbCxtsaaxx4T7tPMrGyhqWIFfkTUWFRWlKEwNxetnVelQr6hvl6+1cqHV+Pvf/uzsAIQKsLdJFMOZAwgfpQ4TWJAS4qLYWVtJZHbmJMxGD9pEubMnSc0Ird7sGqzpakRpMYiRx9TsufOxMDG1hae3nRqVGhuapRNkKOLq3yX3hWj15/XG0TftxW9/tYXwzZQg3un8b8Bbxjo4pv/nWPAytpGUl/fPLphCbeG3jAL4ufvh5rqGjg5O0tUgPARpp+48/b19YeDk1OP18p+QTxu1H936csfWimYa0MDQ6mSZdTe1s5BcL3DffCbk1v34MEDgvllOoyp+ri4CxKJWPPo47AwJ53ZyHRok5KSxJGNnjodP/n/27v2qKjuc7tHARkYXjMD8sYBbaqAxgcSCeIDNJp3X+mq19yspFnpzcptupqmadLVrNWbJrePdVdW05uuXps2aROTpk3SaE1M0lQFFMVXozxEFAERkMfwlrcw7f4YYKAgPkDA+51/BJlzzm/2+Z1zvt/37W/v7z4hShasXlRVVeObj38Lf3hrqywsmXlub2tDUtIKzHBzlyCXL5R1t21EdU01ik4VotZux4MPff36VKUoC1dWhmd/8AysVgtu23C7vCipwsEFe1xcPB7+xqPYs+tv4h40pSgHBoPwy995+03ct+l+VJSXi2LIhdY2qSpVVlZgx7ZtokWdnJKCtalpEz2NL/v4fOelp++BxWJB7II41FSfx/nzVThy5BC+8R+P4eCBfTD5+EopnLSUpYkrJuf9N/CNDLJge+bp78FsNsPH2xtPfu8ZaUjl85jl6Q8++Itk+Bhc5eccQ8qaVKm4TupmmCHBHRfM7u5uuOeLX5ZMZH5eLgLMAchMz8Ajjz6Gt998A6nr1kuybby31tY2bH39VenTWLwsUSh6v/zFi6ioOI+YmLnw8vYW+mJlxTk0N9ajrLxSqEmBFrO8d4/+/Ri+ct99yMs5jpCQENQ1NEg8x3uRFdW4+HisWrVahs3EEhNUb/9hK1YkJUvlpam5SeIvykVSa7aju6fvfJUVcr1efWUL7r7rbjQ2t6DnYpfo2c6PX4zs7GzBjLrtpJj4+QegprYGmzZtwvbt2+W5HBe3ELm5OXjsm4+P2/wck3LQ1t4mHEgDDH3SC2yGmekmlmYN9XUSqIzesHX1l5clFMbUzBQy0dN6oQXtHe2SpZVyqkv2h/xETjR2aDNb2HeTtEhTSICFHNqJz1SM9k25MmVJq19Cg0095PmafH37RPqn0EZKBxu0BkvWBpSVlSIzIwP33vtFePuYpORCukDbhf4VVp8H9ECo4AA6OtrR0dEh3fdcyZ7IyxUeIMtIXJX7+vpJoyEbMchBYoOVwdkYRmxmzHQT/s6Vc9YMOHzoILyMsxAaHokXnn8Oj/3n48jY9VdpkqqqtsscCg8Pl1XuyuSVyMnNlQcRZUtYyrVFReDk6SLJdnCO8cak7Z8t2ob9+7Mx//M3wcfPDwf270dIcAhWJN0qjWRBgUGSWU7PSEdYWDjmzZ0rHKaGxiZUVpSjuLhYyjsUlu4nP3329yPSVMbsVURYGGa4uYn7C1fjWVlZ+Pz8WCkTNTQ0wmz2x9nSUiQm3iIcS1JsViQliSkCFwcM2ClmnXM8B+0dXUhIWIo9u3eLwDa52xS1Ppy9X8qpFLoOMJtx+NAh4WOxYsCyEQOPxKRkcXrhKv5sKTlQC+DhNhOni87IA23xkmWyIAkKDkHBiXxZ+Ozft08yQ1tf/52UEnld83OPYeWqtfL367I5F48sZfHeYmDLEiezK2xivW5NUlfxZeX+cTic99YFeSHxPuP8IZYM2Pm9eC3ZbMWFPBeMLN3xOdzftMlnIOk9fOZN/DKi74uSksR7nUEWdTH5O5vD2CHNMfBeJy+v71l+vUZ1eRfB9R3T3dUNNw9KGfVx4rkoYlMy+wv4oh+Rj3h5pxn3T3Fx8/EH24USNscWg+KSUpwqzMfS5Stgi4pCW0enUMAY1DKJ4u7BhupxH8YVHZDzgvO3uvo8Thbky0KBmcSPdmyHt8kHNy2IRUF+Lma4e2Dt2jTJdk76fDEYcCI/X56L5M9So5vZWVIl+O+atHXw9/MXHW8+2wMmgKdPSiWrouERkbBYA2VBm75nlzzbUlPXoej0aaH3kH7AALKpuUUSShe7O+W+IwecQStNEWpqaxEbGyv2tLwvZxmNCA4OQWN9vfQgUbWHd+jJggLhNnPKrFq1RlzDWCWPtM2RBji+9/Zmpkv8smHjHdi7N0NMFBbGx2P3p3+VhujIqCh5LjFo5jvN32yR/gar2SyGDXw+WwMD5e9Lly0dt/k5ZkA7pBVfgkgXiYf+HyfkbhlWFr7ah+F1Knte8u4eUZZnkp8wIw544II6/2qQB7to3412s47WUMQjOCBe0BR5DgkNHySzj3Tu/rk1QDC/Cnz+ebNt+dXLuHnxElk9Pvnkt5GQkIiy4iJ5+B8+chRmqxW2qEgEWAKltEueGak0DLSXLk3A4UMHZHWac/wz9HR3Y3FCIg5mH5DmNioLdLS3ikC1f4AFpwoLpfxSdu4sjLOM8DR6IjpmrmSpuKpNXJ6IouJiafxhYBseGooHHnxI1CR4X/3vz1/EqVOnYJszB7FxC7Hrb59IhoL7s4R85kwxurs7ERMzT5qASOBnGdnLy4S6OjtS16Zi27b3JVilrSElUbgQCJodgjNFhXLd5syJhsnHhHu/8CW89D8/RvTcz6Gr+6Ks6Ovq6lFTU411qaki/3XkyBEkr1yJBrtdVuBFxWdhsZqxcePt4oTGhw+z5gygN9x+pyhUsPmETmQMol76+YtCFeG5sg9kYf78BbDFzLt+HeIDtIuB6TsoMXhFr99J+LBr85/r6S91fznvsSEVhsmQy7rUs5njH5aAmAR0L3HK4ZJF/XPHtWN8AOgpMXQmR+y1NZLEYYLHzd1D9KTZaNPedgHeJl+poDFgYAVs3KKFa/321D3t7ZVFFxdopASSX9nR2SkyiXyOyDPLZps6C9Cx4o7rMb+H3z9jjelKrpMDuNDSLAtRX3//QVWSKzmG87MNdXa0NDUhMvoKMtX9EqFXcb6Rdhk7oB2nE+lh/r8i4NoCOcEYCIl/J8LCIxAaGiYB1re+/R3s+fRjUWXYl5UlFJaYaBtamluQl58nPCI+QJnRX716LXb85X1YrUFCwOfIZ8x0R0lpCYyeRswyegoHjHy6iIgosSNkZzob2fz9/CSbQ153cGiokPap6nCmpBgL5i+QYLO6qhJPf/9ZeDq7T//vly8L12jxsgQYZ3nis6OHELdokayeCwsK0NHZJWLVXIlnZGag92K3BJRe3ibk5+cJob6hsUGqF3ypWa1WNDY2StWEq3RmekltoSMZG0Ze/OkLkl0OMFuEQsDxsUOaWZwFcQuluYHZ6sa6WlRVV8NeVy9qCWlpaSgsLJTmvf170xEbvxBp6zdix/b38e4f38Km+x+Qjt/MzHQpX7m5eWBvxm7J0JObKC8o3RQBRWAcERiuSTqyluiUCWZH/eYjtMhPSIJsHKG/EQ81DovO4fL1kwGTBrSTgbqec8IQYBnrcHYWFi5eJpkJ8szYsMLKwpmi08JB+txN89HU2CCBI5sHmX1mEMjMKPlcVHBgiYccr32Zmaits0spnStQ8hYtVqtoV1I/1mTyxcmCvsCY+3BfBoGhoeEoPJkvWQiL2SJlIQZ4EVE2IfBzY/DJMhu5rywnMcNLztTJvONCsk9ccatQfRiY0rGlvLQUoeEREpxTmovZz4ryMhgcveLf7evrj8ryMrCRIMpmE5oLy6X8l8fY8vJLiFt0M6Lm2CRzQ81ZBrdUEZnlaRRlEJayuBiQbtWmRoRHzhH5n87OPk3o53/0Qzz11Pclo1JXX4d6e62Uv8nPYvDP7DN518SaWHKh8LV/u3/qZFwmbObpgRUBRUARUAQmEwENaCcTfT33uCNAI5DGhnrhF/r4+g6qHFzWmYY2ghWeyBcOsTVotkgn0QxjcHN+dsSmsOFOKa67uQidu6oEOD/icPSisa4O7rNmCQeub7vE8YZ8r5Ea2Zz7OhwiaWWLmTsomj1ciHuIqKDrgfuOQXWKkuJi4dH20yYGRAhdVCQYcJNTSb4XOZ8shU79TNFlTRD9kCKgCCgCisAURUAD2il6YXRY14DAOJRP5OwDAedgUPgvpgQjDtM1AL2UWsK/Bo0D53XtshtyjpFKdK5B70gDcpExczWKuNLS3hCO6hgc59EkwK7hsuquioAioAgoAorAaAhoQKtzQxEYAwEqe1DZgfxZKjhQhoSqCOxAp3oBVRNoAsIuTnpdh4WHCcWh1l4Dc4AF58rPwdfHFwEB/ig+c0YCZSonsFuZotL9ag7Sre50FuM5SF2QTKjL1tHOjvJucVJjkxb1BenkEhERKY1hA5szoKRYPMdMNQnKplGmzGoNRE/vRaFN9HV1jxUQ6xRRBBQBRUARUASmNgIa0E7t66OjmwIIUA2ARiLUDf7J88+JY1r8wptx+PBBsSSMjokW69+ykhKx/n3iu0+jq7MDH324A8Ehofjk451inRgfvwhvvPEGli1PRPDsIFEC2Lz538VQghaBgUHBOF9ZIUoFp0+dFMmu1WtpCuKkKRhmYG/6Huz8cAee/a8f4b+ff064sNTdXb48ERvuuEuayBhMt7VekG7i6n/Ktrz7ztvi0PLJRzthi45GtC1a+LrzF8SL+57dXoOQkLDrp0YwBa6pDkERUAQUAUXgxkJAA9ob63rqt5kABKgD+9qrr6C0pBgpKSlIWZMmentV1IK9NVmcb8ixpatM/KJF4uaSmZ4Oh6NHkp/kndIxzcPojYLc41i9Zg0qq2rEfMDTwx3+FgtWJKfgbEkJfvubX4uI9vrbNuDN13+HJ5562pnBNYge9JZf/QIOxwzccfc9+M2vt2BtairOlZaI5t99mzaj52I3svbtlXPefc+9yMjMFNH4ZQkJOFV4EmEhIWJCcsutK6WZ68Md2yXLTHOU8LCwydd+nIDrp4dUBBQBRUARuPER0ID2xr/G+g2vEYHGxib87KcviAg1HU6WLFkmdp5GT09xOOu52Cs2gPv3ZeKhRx6VBii6JVHNoKvrolALTF5GydZS5JzarQxgqShANQCqBwQGBokL13vv/AmxsfG48667kLlnl4h3U2uS27GjR/H7378mn6XTy4GD2RL8FhacwFe++jWxQKS727Z3/4jIyCgsXLxE5Lz+/N472Hj7nSg/Vy6i5lR6oDpDbFycuN5QT/fBrz+MqKgoDWivca7o7oqAIqAIKAKTg4AGtJODu551GiHADO2nn3wkFqN/fu9PCJ49W9zMKElFqS/6e1stZhGnvpke5A5g965PJTgkh5XyXQxmzRaLOKp0dnUhOWUVamuq0N7WgZKSYuG5btr8gLjv0d2K+77221ewafP9Yuowb95NeGvr62KiwHOeyMsRfdmHH3kUxz47ioaGeqxbv0HUHVrbWnG+ohz+/v7w9DLh4507sGpNqjjmZaTvFh1bOuBQf5ZcXrre0N1MlQim0aTUoSoCioAioAgMQUADWp0QisAYCDCDSs1ZOnTRipBuPDRHoLVgaWmJBJv0sXbz8ISbs4mLQeKhA1lIW78B9vo6+Jh8JJCsqqyA0csIs9mK+no7vL1NInFF61M2jvVbANdUVyE/L0fsgukmdktSElpbWmD08pa+MboEURLLJNaivehsb4OXt89Ag1m/BgEDavJpjV5eMvbm5mZpaOP+vn7+zvEOd4jTKaEIKAKKgCKgCEwvBDSgnV7XS0c7KQiIEf2gOYAoCLjKcfXLenFwzp8NBtTb7fDzD8BMNzfnvrQBpWqBo+93+Zm/8mfnv/IfBrS0NMPL21uUFAY/079vv6QY92HDmOv4hstpufxtQHbL1Y70KiyGJ+Ua6EkVAUVAEVAEFIHRERg5oB0vHU9FXhFQBBQBRUARUAQUAUVAEZhgBIYGtAaDSP0c2JuO+ro6bRCZYPD18IqAIqAIKAKKgCKgCCgCV4ZAb08PAoNnI3lVWp8HEmuVjt6eITVH+r6fLS1GR3u7+MjrpggoAoqAIqAIKAKKgCKgCEwVBHodvTCZTIiyxQwkX0ehHAx1J5oqX0DHoQgoAoqAIqAIKAKKgCKgCAz0ozih0KYwnROKgCKgCCgCioAioAgoAtMaAQ1op/Xl08ErAoqAIqAIKAKKgCKgCGhAq3NAEVAEFAFFQBFQBBQBRWBaI6AB7bS+fDp4RUARUAQUAUVAEVAEFAENaHUOKAKKgCKgCCgCioAioAhMawQ0oJ3Wl08HrwgoAoqAIqAIKAKKgCKgAa3OAUVAEVAEFAFFQBFQBBSBaY3APwBZrNBkaRjHEAAAAABJRU5ErkJggg==\" width=\"584\" height=\"178\"\u003e\u003c/p\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Processing and Isolation of Breast Cancer Tissue Samples\u003c/h2\u003e\u003cp\u003eBreast cancer tissue samples were collected from fresh, surgically resected tumor tissues within 30 min post-resection. The samples were rinsed twice with sterile saline solution to remove adherent blood and surface contaminants. Cancerous tissues and adjacent normal control tissues were sampled, carefully avoiding areas with hemorrhage or necrosis. The sampled tissues were promptly placed in tissue preservation solution (bioGenous, Suzhou, China) and transported to the laboratory under low-temperature conditions. These steps were performed by professional pathologists.\u003c/p\u003e\u003cp\u003eThe collected tumor and normal breast samples underwent further processing in a sterile biosafety cabinet. The samples were rinsed twice with pre-cooled sterile Hank's Balanced Salt Solution (HBSS, Pricella, Wuhan, China). Sterile ophthalmic scissors were used to carefully remove unwanted tissues such as fat. The tissues were divided into three parts. One part was rapidly frozen in liquid nitrogen and stored at -80\u0026deg;C for molecular biology and biochemical analyses. Another part was fixed with 4% paraformaldehyde for morphological observation and analysis. The remaining part was used for the culture of breast cancer organoids.\u003c/p\u003e\u003cp\u003eFor the breast cancer tissues intended for organoid culture, sterile ophthalmic scissors were used to cut the tissues into small cubes of approximately 1 mm\u0026sup3;. The tissue pieces were added to a container containing tissue digestion solution (Accurate International, Guangzhou, China) and placed in a 37\u0026deg;C shaking incubator for approximately 15\u0026ndash;30 min. Once most of the cell clusters were dissociated, the reaction was terminated with HBSS solution. The digested tissue suspension was filtered through a 100 \u0026micro;m cell strainer. The filtrate was centrifuged at 180 \u0026times;g for 3 min, and the supernatant was discarded. The cell pellet was washed with HBSS solution and centrifuged again. The pellet was resuspended in Matrigel matrix (Corning, New York, US) and approximately 30\u0026ndash;50 \u0026micro;l of the cell suspension was added to each well of a 37\u0026deg;C preheated 24-well plate. The plate was inverted and placed in a constant-temperature CO₂ cell culture incubator. Once the Matrigel solidified, different formulations of breast cancer organoid medium were added to each well for culture.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Cultivation, Passage, Cryopreservation, and Revival of Breast Cancer Organoids\u003c/h2\u003e\u003cp\u003eBreast cancer organoids were cultured, and fresh medium was replaced every 2 days. When the organoids reached a diameter of approximately 200 \u0026micro;m and exhibited good growth status, they were passaged. The medium was discarded, and the organoids were gently washed with PBS. The organoids were digested with a specialized organoid digestion solution (bioGenous) to disperse them into small cell clusters. The cells were collected by centrifugation and inoculated into fresh Matrigel at a specific ratio for continued culture.\u003c/p\u003e\u003cp\u003eWhen the breast cancer organoids grew and reached a diameter of approximately 200 \u0026micro;m, they were frozen for long-term preservation. First, the Matrigel encapsulating the organoids was disrupted using a pipette tip, and a cell recovery solution (Corning) was added to remove the Matrigel components. The organoid cell clusters were collected by centrifugation, resuspended in organoid cryopreservation medium (bioGenous), and transferred to cryogenic vials. The vials were placed in a programmed freezing container and stored at -80\u0026deg;C overnight before being transferred to a liquid nitrogen tank for long-term preservation.\u003c/p\u003e\u003cp\u003eFor the thawing of breast cancer organoids, a method similar to that used for 2D cell lines was used. The frozen organoids were retrieved from the liquid nitrogen tank and rapidly thawed in a preheated 37\u0026deg;C water bath. The thawed cells were collected by centrifugation and resuspended in Matrigel before being inoculated into 24-well plates at a specific density for subsequent culture.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Histology and Immunohistochemistry\u003c/h2\u003e\u003cp\u003eThe tissues were fixed in 4% paraformaldehyde overnight, followed by dehydration and embedding in paraffin. Organoids were stained with eosin, pre-embedded in 3% agarose gel, and fixed in 4% paraformaldehyde for 30 min.\u003c/p\u003e\u003cp\u003eStaining was conducted 4 \u0026micro;m-thick paraffin sections. Following routine dewaxing and hydration, H\u0026amp;E staining was performed using standard methods. The sections were then subjected to histopathological evaluation.\u003c/p\u003e\u003cp\u003eFor immunohistochemical staining, sections were subjected to citrate high-pressure retrieval at pH 6.0 (ZSGB-BIO, Beijing, China). Staining was performed using a two-step universal kit (ZSGB-BIO, PV8000). The primary antibodies included Ki-67 (ZSGB-BIO), anti-ER (ZSGB-BIO,), anti-PR (ZSGB-BIO), and anti-HER2 (Roche, Basel, Switzerland), all diluted to specific ratios. Images were captured using an Olympus microscope. Semi-quantitative analysis of immunostaining was performed by certified pathologists using the H-score system as follows: H-score (range 0\u0026ndash;12)\u0026thinsp;=\u0026thinsp;proportion of positive cells (0\u0026ndash;4 points) \u0026times; staining intensity (0\u0026ndash;3 points).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.5 Drug Sensitivity Analysis\u003c/h2\u003e\u003cp\u003e We first reviewed the medication history and imaging data of breast cancer patients with different molecular subtypes and conducted an in-depth analysis of the impact of various medication regimens on the disease progression in conjunction with pathological diagnoses and imaging records. We then assessed the sensitivity of patients to different drugs.\u003c/p\u003e\u003cp\u003eBreast cancer organoids of different molecular subtypes were digested, uniformly seeded into 96-well plates at a density of 3000 cells per well, and grown to a stable state. Organoids were treated with different concentrations of drugs such as Carboplatin (0.01-50 \u0026micro;M), Paclitaxel (0.001-50 \u0026micro;M), Doxorubicin (0.01\u0026ndash;100 \u0026micro;M) and Cyclophosphamide (0.01\u0026ndash;200 \u0026micro;M), which commonly used in the clinical setting for patients with different molecular subtypes of breast cancer for approximately 48 h. Cell viability was evaluated using the Alamar Blue\u0026trade; Cell Viability Assay Kit (Invitrogen, Carlsbad, CA, USA) and a microplate reader (Molecular Devices, California, US). We plotted the IC50 curves for each drug group and calculated the corresponding cell viability values.\u003c/p\u003e\u003c/div\u003e"},{"header":"3 Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e3.1 Construction of Breast Cancer Organoids with Different Molecular Subtypes Using Commercially Available Media\u003c/h2\u003e\u003cp\u003eA schematic diagram to illustrate the construction of the breast cancer organoid system is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA. We first evaluated the efficacy of four commercial media (from Manufacturers A\u0026ndash;D) in generating breast cancer organoids from Luminal A, Luminal B, HER2-positive, and triple-negative breast cancer (TNBC) samples (\u003cb\u003eSupplementary Fig.\u0026nbsp;1\u003c/b\u003e). The medium from Manufacturer A was largely ineffective in forming organoid spheres. While media from Manufacturers B and C induced the formation of organoid spheres in the short term, structural collapse occurred on day 36 and day 54, respectively. The medium from Manufacturer D was able to stably maintain the growth of all subtype organoids, with a success rate exceeding 90%. The formed organoids were transparent, solid spherical structures with good growth status, and they maintained morphological stability after four consecutive passages. In freeze-thaw experiments, only the growth of HER2-positive organoids was slightly compromised, while organoids of other molecular subtypes maintained robust growth (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). These results showed that the medium from Manufacturer D can effectively support the long-term expansion, culture, and cryopreservation of breast cancer organoids across different molecular subtypes.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e3.2 Molecular and Histopathological Discordances in above Commercially Cultured Breast Cancer Organoids\u003c/h2\u003e\u003cp\u003eWe next systematically evaluated the morphological and molecular marker consistency between the breast cancer organoids constructed using commercially available media and their parental tumor tissues. Paraffin sections of the organoids were subjected to H\u0026amp;E staining and immunohistochemical analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). H\u0026amp;E staining results demonstrated that the organoids of all molecular subtypes effectively recapitulated the cell morphology and histological features of parental tissues, including nuclear enlargement, hyperchromasia, and glandular or solid growth patterns. However, immunohistochemical analysis revealed slightly elevated Ki67 expression in organoids compared with parental tissues, along with a pronounced subtype-dependent molecular marker deviation. Except for the stable maintenance of ER/PR/HER2 triple negative phenotype in TNBC organoids (with a 100% compliance rate), all other subtypes exhibited abnormal expression of characteristic molecular markers ER/PR/HER2 (immune score dropped to 0) (\u003cb\u003eSupplementary Fig.\u0026nbsp;2\u003c/b\u003e). These findings indicate that while the commercially available culture medium systems can support the morphological maintenance and expansion of breast cancer organoids in vitro, they struggle to stably preserve the expression profiles of key biomarkers specific to each molecular subtype during long-term culture.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.3 The Effect of FGF-free Conditions Combined with EV on the Breast Cancer Organoid Systems\u003c/h2\u003e\u003cp\u003eOn the basis of prior bioinformatics screening, we selected HER2-positive (HR-positive) breast cancer samples with positive molecular markers and evaluated the impact of FGF and different estrogen forms (estradiol (ES)/estradiol valerate (EV)) on the stability of molecular characteristics in breast cancer organoids. FGF supplementation significantly impaired organoid growth, inhibiting three-dimensional proliferation (Day 6 diameter: 195\u0026thinsp;\u0026plusmn;\u0026thinsp;22 \u0026micro;m vs. 325\u0026thinsp;\u0026plusmn;\u0026thinsp;28 \u0026micro;m in the FGF-free group, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and inducing adherent differentiation in more than half of the organoids (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA\u0026ndash;B), likely attributable to FGF activity.\u003c/p\u003e\u003cp\u003eTo compare the effects of ES and EV on breast cancer organoids, we used P5 organoids. Bright-field microscopy and HE staining revealed no significant differences in organoid spheroid morphology, size, or optical transparency between the two groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC\u0026ndash;D). Immunohistochemical staining demonstrated that compared with the EV group, in the ES group, the ER/PR expression was nearly lost by passage 5; this is likely because of the short metabolic half-life of ES (\u0026lt;\u0026thinsp;48 h in vitro activity maintenance). In contrast, the EV group maintained stable ER\u003csup\u003e+\u003c/sup\u003e/PR\u003csup\u003e+\u003c/sup\u003e phenotype through esterified sustained-release properties, showing high consistency with primary tumors after 5 passages (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD\u0026ndash;E). These findings suggest that the FGF-free culture system combined with EV can concomitantly mitigate FGF-induced mesenchymal transition and ES metabolic impairment.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.4 Screening of EV concentrations in breast cancer organoids of distinct molecular subtypes\u003c/h2\u003e\u003cp\u003eTo investigate the optimal EV concentration for the EV culture system, we carefully selected HER2-positive (HR-positive) breast cancer samples with positive molecular markers and cultured them in media supplemented with 0\u0026ndash;50 \u0026micro;M EV. The results of the bright-field showed that the 50 \u0026micro;M group showed restricted proliferation and adherent differentiation, while the 0\u0026ndash;20 \u0026micro;M groups maintained typical 3D spheroidal growth. H\u0026amp;E staining demonstrated that all groups maintained the histological architecture and nuclear atypia of primary tumors (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA). Semi-quantitative immunohistochemical analysis demonstrated that ER/PR/HER2 positivity in the 20 \u0026micro;M and 50 \u0026micro;M groups closely matched those of primary tumors, while the 0 \u0026micro;M and 10 \u0026micro;M groups exhibited complete loss of these markers. Additionally, the Ki67 proliferation index was comparable or even higher in organoids than that in primary tumor tissues (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA\u0026ndash;B). Collectively, these findings indicate that 20 \u0026micro;M estradiol valerate-containing medium achieves an optimal balance between organoid proliferative activity and molecular phenotype stability, providing critical culture parameters for constructing molecular subtype-specific breast cancer models.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e3.5 Application of FGF-Free\u0026thinsp;+\u0026thinsp;EV (20 \u0026micro;M) Culture System in Various Molecular Subtypes of Breast Cancer Organoids\u003c/b\u003e\u003c/p\u003e\u003cp\u003eUsing the FGF-free\u0026thinsp;+\u0026thinsp;20 \u0026micro;M EV culture system, we successfully established organoid models of triple-negative breast cancer, Luminal, and HER2\u003csup\u003e+\u003c/sup\u003e breast cancer. After 10 days of three-dimensional culture, organoids of all three subtypes developed translucent, solid spherical structures, maintaining\u0026thinsp;\u0026gt;\u0026thinsp;90% morphological stability even after five passages. H\u0026amp;E staining demonstrated that the organoids preserved the cellular morphological and structural characteristics of the primary tumors (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA\u0026ndash;C). Semi-quantitative immunohistochemical analysis confirmed that all organoids retained their parental molecular characteristics: the TNBC group showed 100% concordance with triple-negative status tissue, while Luminal A and HER2\u003csup\u003e+\u003c/sup\u003e (HR\u003csup\u003e+\u003c/sup\u003e) organoids expressed their respective characteristic molecular markers, along with slightly reduced IHC scores (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eD). This confirms the development of a system that overcomes the limitations of conventional media that lead to loss of subtype-specific features.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e3.6 The Relationship between Personalized Drug Sensitivity Testing in Breast Cancer Organoids of Different Molecular Subtypes and Real-World Patient Treatment Efficacy\u003c/b\u003e\u003c/p\u003e\u003cp\u003eWe retrieved preoperative medication regimens and imaging data from clinical patients corresponding to the successfully generated triple-negative breast cancer, Luminal, and HER2\u003csup\u003e+\u003c/sup\u003e breast cancer organoid models. Drug sensitivity testing was performed in these organoid models, and the results were compared with the changes in tumor lesions observed in the imaging data of clinical patients before and after treatment. CT imaging results of TNBC patients showed a significant reduction in tumor lesions after 6 cycles of combined treatment with paclitaxel (albumin-bound) and carboplatin. Drug sensitivity testing in TNBC organoid models revealed the strongest sensitivity to carboplatin, followed by paclitaxel, while anthracycline doxorubicin exhibited the poorest efficacy, consistent with the clinical sensitivity of patients to the ACT regimen (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eA). Ultrasound results of Luminal A patients demonstrated a 27.2% reduction in the maximum tumor area after 6 cycles of ACT treatment, indicating a certain degree of sensitivity. Similarly, drug screening in organoid models showed the strongest sensitivity to paclitaxel, while cyclophosphamide and doxorubicin had no significant efficacy, aligning with the clinical sensitivity of patients to the treatment regimen (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eB). Ultrasound results of HER2\u003csup\u003e+\u003c/sup\u003e (HR\u003csup\u003e+\u003c/sup\u003e) patients revealed almost no change in tumor volume after 4 cycles of TCbHP treatment (paclitaxel (albumin-bound)\u0026thinsp;+\u0026thinsp;carboplatin\u0026thinsp;+\u0026thinsp;trastuzumab\u0026thinsp;+\u0026thinsp;pertuzumab), suggesting a certain degree of drug resistance. Consistent with these results, drug screening in organoid models showed poor sensitivity to paclitaxel, carboplatin, and trastuzumab, matching the drug resistance observed in clinical patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eC).\u003c/p\u003e\u003cp\u003eThese results demonstrated that the drug sensitivity results of breast cancer organoids with different molecular subtypes were generally consistent with real-world clinical outcomes, indicating that this model can accurately guide the selection of personalized treatment regimens and provide experimental evidence for the translation of precision medicine in breast cancer.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eBreast cancer, a highly heterogeneous disease, necessitates personalized treatment strategies tailored to its molecular subtypes. Breast cancer is categorized into subtypes on the basis of hormone receptor (ER, PR) and HER2 expression status such as Luminal A, Luminal B, HER2-positive, and triple-negative, each exhibiting distinct biological behaviors and therapeutic responses \u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. This molecular heterogeneity significantly complicates clinical management. For instance, luminal breast cancers generally respond well to endocrine therapy, whereas triple-negative breast cancers are treated with chemotherapy and targeted therapies. However, even within the same molecular subtype, patient responses to treatment vary considerably, further increasing the challenges of clinical intervention. Therefore, developing experimental models capable of mimicking tumor heterogeneity and predicting therapeutic responses has become an urgent need in current breast cancer research \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn recent years, organoid models have emerged as a novel in vitro research tool. Organoids effectively preserve the molecular characteristics and heterogeneity of parental tissues and have become a powerful tool for studying tumor biology, drug sensitivity, and personalized medicine \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. However, the efficacy of organoid culture systems heavily relies on the optimization of culture conditions, particularly the selection of media and growth factors, which remains a key challenge in this field.\u003c/p\u003e\u003cp\u003eThrough systematic screening of commercially available media, our study revealed that most media struggled to sustain the long-term growth of breast cancer organoids, with organoids tending to lose the molecular subtype features of their parental tissues during culture. Consistent with previous reports \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e, we observed that Manufacturer A\u0026rsquo;s medium was largely ineffective in promoting organoid formation across tested samples, underscoring the crucial role of specific growth factor combinations in organoid initiation and maintenance. While the media from Manufacturers B and C induced organoid formation in the short term, they exhibited certain limitations in maintaining long-term organoid survival and functional integrity. In contrast, Manufacturer D\u0026rsquo;s medium demonstrated superior performance, enabling robust organoid formation and stable growth across all molecular subtypes with a success rate exceeding 90%. These findings align with a growing body of literature emphasizing the importance of defined serum-free medium formulations in preserving the genetic and phenotypic stability of cancer organoids \u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eBy comparing the growth status and molecular marker expression of organoids under different media, our study further confirmed and elucidated the limitations of existing media in maintaining the molecular subtype features of breast cancer organoids. Despite organoids retaining tumor cell morphology when cultured in Manufacturer D\u0026rsquo;s medium, immunohistochemical analysis revealed a loss of subtype-specific molecular markers in Luminal A, Luminal B, and HER2-positive organoids after passaging. This observation is consistent with previous studies reporting similar challenges in maintaining molecular fidelity during long-term organoid culture \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. Notably, TNBC organoids exhibited remarkable stability in preserving their triple-negative phenotype, suggesting that the molecular mechanisms underlying subtype stability may vary across different cancer subtypes. The increased Ki67 expression in organoids compared with parental tumors may be attributed to the enrichment of breast cancer stem cells in vitro. These findings highlight the necessity for further optimizing culture conditions.\u003c/p\u003e\u003cp\u003eBreast cancer with HER2 overexpression is a clinically aggressive subtype associated with poor prognosis. Notably, approximately 50% of HER2\u0026thinsp;+\u0026thinsp;tumors co-express hormone receptors (HR), constituting a distinct molecular subtype characterized by dual positivity for HER2 and estrogen/progesterone receptors. We next obtained HER2\u003csup\u003e+\u003c/sup\u003e/HR\u003csup\u003e+\u003c/sup\u003e patient-derived tumor samples and evaluated the impact of FGF and estrogen supplementation on maintaining the phenotypic stability of organoid cultures. Our data indicated that FGF supplements, commonly used in organoid culture protocols, significantly impaired organoid growth and induced adhesion, likely as a result of pro-differentiating effects. This finding aligns with recent reports that FGF promotes cell proliferation by activating MAPK and PI3K/AKT signaling pathways, but its overactivation may lead to the loss of original molecular features in organoids \u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. Estradiol and EV, both estrogen analogs, play crucial roles in the growth and differentiation of breast cancer cells \u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. The long-acting estrogen derivative EV demonstrated superiority over estradiol in maintaining ER/PR expression across multiple passages. This observation can be attributed to the esterified form of EV, which provides sustained release of bioactive estrogen, thereby overcoming the rapid metabolic clearance of estradiol in vitro. Our data support the notion that EV supplementation can effectively preserve hormone receptor expression in ER-positive breast cancer organoids, as previously reported in other model systems \u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eOn the basis of the above findings, we further optimized the EV concentration in the FGF-free culture system and determined that 20 \u0026micro;M was the optimal concentration for balancing organoid proliferation and molecular phenotype stability. This concentration not only supported robust organoid growth but also preserved the subtype-specific molecular features of HER2\u003csup\u003e+\u003c/sup\u003e (HR\u003csup\u003e+\u003c/sup\u003e) organoids. This finding is consistent with the study by Hortobagyi \u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e, who demonstrated that estrogen exerts dose-dependent effects on breast cancer cell proliferation and differentiation by activating ERα and ERβ signaling pathways. Low concentrations of estrogen primarily promote cell proliferation through ERα, while high concentrations may induce cell differentiation through ERβ or non-classical signaling pathways such as PI3K/AKT and MAPK. Additionally, high concentrations of EV may further influence organoid growth patterns by altering the composition or stiffness of the extracellular matrix (ECM) \u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. These mechanisms provide a theoretical basis for the role of EV in breast cancer organoid culture and offer new directions for future medium optimization.\u003c/p\u003e\u003cp\u003eTo validate the reliability of the FGF-free EV culture medium system, we conducted cultivation assays using breast cancer samples of distinct molecular subtypes: triple-negative, Luminal, and HER2-positive. All three subtypes exhibited sustained growth, maintained robust morphological integrity, and preserved the molecular specificity characteristic of their parental tissues. These findings underscore the superior performance of this novel medium system in supporting the long-term expansion of organoids derived from diverse breast cancer molecular classifications.\u003c/p\u003e\u003cp\u003eIn recent years, chemotherapy has emerged as a cornerstone in the multimodal treatment of breast cancer, particularly within the context of neoadjuvant therapy. As outlined in the Expert Consensus on Neoadjuvant Therapy for Breast Cancer and international St. Gallen guidelines, chemotherapy regimen selection must adhere to the precision medicine paradigm of \u0026ldquo;molecular subtyping-efficacy prediction.\u0026rdquo; We next developed a drug sensitivity prediction model using our established organoid culture system, which included triple-negative, Luminal, and HER2-positive breast cancer subtypes. This innovative approach establishes a correlation validation framework between organoid responses and patient treatment outcomes. Our data demonstrated a notable consistency between drug responses in organoids of different cancer subtypes and clinical outcomes. TNBC organoids exhibited higher sensitivity to carboplatin, reflecting significant tumor regression observed in patients receiving ACT regimens \u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. Similarly, Luminal A organoids showed the highest sensitivity to paclitaxel, correlating with modest tumor reduction in patients receiving the same treatment \u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. HER2-positive organoids demonstrated poor sensitivity to TCbHP, which indicated a lack of response in patients. These findings are consistent with previous studies demonstrating the predictive value and potential applications of cancer organoids in patient drug responses \u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn conclusion, our study emphasizes the critical importance of medium optimization in establishing high-fidelity cancer organoid models that accurately reflect the molecular and functional features of parental tumors. The FGF-free\u0026thinsp;+\u0026thinsp;EV culture system introduced in this paper represents an advancement in breast cancer organoid technology, providing a foundation for drug discovery, biomarker development, and personalized treatment planning. Despite the significant findings described here, this study has several limitations. First, the sample size was small and did not cover all breast cancer molecular subtypes; future studies should expand the sample size and explore culture conditions for other subtypes. Second, this study did not delve into the mechanisms underlying the role of EV in organoid culture; future research should pursue multi-omics technologies (such as transcriptomics and proteomics) for systematic analysis. Furthermore, optimization of other medium components (such as growth factors and Matrigel) \u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e warrants further investigation. In the future, we will focus on exploring medium components and mechanisms of action, optimizing culture conditions to enhance the molecular stability of organoids, expanding the scope of tested drugs to cover emerging therapies, and validating the clinical utility of organoid-based drug sensitivity testing in prospective clinical trials.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical Approval and Consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study followed the Declaration of Helsinki and received ethical approval from the Tianjin Fifth Central Hospital IRB (Approval No.: WZX-EC-KY2024036, Date: 06/27/2024). All participants provided written informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors have reviewed and approved the final manuscript for publication, confirming its accuracy and originality.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of supporting data\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available in the Manuscript and Additional files of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by grant from Tianjin Municipal Education Commission\u0026apos;s research project (2023KJ121).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eChunyan Zhang: Methodology, Validation, Writing-original draft, Project administration.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBing Han: Methodology, Validation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eZhihua Jia: Resources.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMin Liu: Validation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eYanxia Li: Formal analysis.\u003c/p\u003e\n\u003cp\u003eJie Xu: Formal analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eJie Zheng: Validation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eYajing Sun: Validation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eYuting Le: Resources.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eShupeng Zhang: Writing-original draft.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eZhijiang Shao: Data curation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eJian Wang: Writing-review and editing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eXiaozhi Liu: Conceptualization.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Gabrielle White Wolf, PhD, from Liwen Bianji (Edanz) (www.liwenbianji.cn) for editing the English text of a draft of this manuscript. We also acknowledge the supports of The National Clinical Key Specialty Construction Project of the Emergency Department (No. 2023283) and The Tianjin Key Medical Discipline (Specialty) Construction Project (No. TJYXZDXK-079D).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eKim J, Harper A, McCormack V, et al. Global patterns and trends in breast cancer incidence and mortality across 185 countries. Nat Med. 2025;31(4):1154-1162. doi:10.1038/s41591-025-03502-3Britt KL, Cuzick J, Phillips KA. Key steps for effective breast cancer prevention. \u003cem\u003eNat Rev Cancer\u003c/em\u003e. 2020;20(8):417-436. doi:10.1038/s41568-020-0266-x\u003c/li\u003e\n \u003cli\u003eBritt KL, Cuzick J, Phillips KA. Key steps for effective breast cancer prevention. Nat Rev Cancer. 2020;20(8):417-436. doi:10.1038/s41568-020-0266-x\u003c/li\u003e\n \u003cli\u003eFerro A, Campora M, Caldara A, et al. 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Designer matrices for intestinal stem cell and organoid culture. \u003cem\u003eNature\u003c/em\u003e. 2016;539(7630):560-564. doi:10.1038/nature20168\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"cancer-cell-international","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ccin","sideBox":"Learn more about [Cancer Cell International](http://cancerci.biomedcentral.com/)","snPcode":"12935","submissionUrl":"https://submission.nature.com/new-submission/12935/3","title":"Cancer Cell International","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Breast Cancer Organoids, Molecular Subtypes, FGF-Free Culture System, Estradiol Valerate, Precision Drug Screening","lastPublishedDoi":"10.21203/rs.3.rs-6906829/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6906829/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBreast cancer, a prevalent malignancy among women, exhibits high heterogeneity, highlighting the critical need for personalized treatment strategies. Breast cancer organoids (BCOs), an emerging in vitro research tool, closely mimic the biological characteristics of tumors and demonstrate distinct differences in therapeutic response, prognosis, and biological features. However, the incomplete culture system of BCOs is still a challenging aspect of current research. In order to further optimize the existing culture formula of BCOs, we collected tumor tissue samples from breast cancer patients with various molecular subtypes, including Luminal A, Luminal B, HER2 overexpressing (HER2\u003csup\u003e+\u003c/sup\u003e), and triple-negative breast cancer (TNBC). The samples were extracted and cultured using commercially available media. We observed that some media failed to sustain the growth of breast cancer organoids, while others, although supporting organoid survival, led to the loss of parental molecular subtype characteristics in most cases. Through literature review and screening of key factors, we developed an FGF-free estradiol valerate (EV) culture system. Using triple-positive breast cancer samples, we optimized the concentration of EV. Our results indicated that 0, 10, and 20 \u0026micro;M EV maintained normal organoid growth, whereas 50 \u0026micro;M EV promoted adherent differentiation, which is detrimental to long-term organoid culture. Further analysis revealed that 20 \u0026micro;M EV not only preserved the organoid cellular morphology but also retained the parental molecular subtype features. Using this optimized culture system, we successfully cultivated breast cancer organoids from TNBC, Luminal, and HER2\u003csup\u003e+\u003c/sup\u003e samples. We then developed a drug sensitivity prediction model using our established organoid culture system, which included triple-negative, Luminal, and HER2-positive breast cancer subtypes. By comparing imaging data before and after clinical treatment, we found a high concordance between drug sensitivity in the organoid model and clinical efficacy. This study provides an optimized culture medium system for the cultivation of breast cancer organoids and validates its potential application in precision drug screening. This model promises to deliver precise and effective treatment strategies for breast cancer patients, further improving their prognosis and quality of life, and ushering in a new chapter in personalized breast cancer treatment.\u003c/p\u003e","manuscriptTitle":"Molecular Subtype-Specific Breast Cancer Organoids: Development of an FGF-Free Estradiol Valerate Culture System for Precision Drug Screening","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-07 07:09:13","doi":"10.21203/rs.3.rs-6906829/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-20T16:35:58+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-20T08:50:16+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-15T19:33:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"227589688777319154549477584212425899034","date":"2025-10-14T12:01:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"86049789479135882012482789864340775318","date":"2025-10-14T09:35:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"83390454652876741897642290976108560748","date":"2025-09-26T07:37:10+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-05T00:40:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-17T04:31:03+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-17T04:29:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cancer Cell International","date":"2025-06-16T15:04:03+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cancer-cell-international","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ccin","sideBox":"Learn more about [Cancer Cell International](http://cancerci.biomedcentral.com/)","snPcode":"12935","submissionUrl":"https://submission.nature.com/new-submission/12935/3","title":"Cancer Cell International","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"dd50c56c-7489-4fef-b2cd-d0cf52d140cd","owner":[],"postedDate":"August 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-12T16:02:57+00:00","versionOfRecord":{"articleIdentity":"rs-6906829","link":"https://doi.org/10.1186/s12935-025-04160-8","journal":{"identity":"cancer-cell-international","isVorOnly":false,"title":"Cancer Cell International"},"publishedOn":"2026-01-08 15:58:01","publishedOnDateReadable":"January 8th, 2026"},"versionCreatedAt":"2025-08-07 07:09:13","video":"","vorDoi":"10.1186/s12935-025-04160-8","vorDoiUrl":"https://doi.org/10.1186/s12935-025-04160-8","workflowStages":[]},"version":"v1","identity":"rs-6906829","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6906829","identity":"rs-6906829","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}