Coronary Flow Reserve increase after Dapagliflozin Treatment in patients with type 2 diabetes is maintained after 4 years: a 4-Year DAPAHEART Follow-up Study

Coronary Flow Reserve increase after Dapagliflozin Treatment in patients with type 2 diabetes is maintained after 4 years: a 4-Year DAPAHEART Follow-up Study | 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 Coronary Flow Reserve increase after Dapagliflozin Treatment in patients with type 2 diabetes is maintained after 4 years: a 4-Year DAPAHEART Follow-up Study Francesca Cinti, Cassandra Morciano, Andrea Guarneri, Luigi Cappannoli, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6758884/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 31 Aug, 2025 Read the published version in Cardiovascular Diabetology → Version 1 posted 18 You are reading this latest preprint version Abstract Background Cardiovascular (CV) outcome trials have shown that sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce CV mortality in type 2 diabetes (T2DM). We previously found that 4 weeks of SGLT2i treatment increased coronary flow reserve (CFR) by 30% and reduced epicardial adipose tissue (EAT) thickness by 19% in T2DM patients with stable coronary artery disease (CAD). However, long-term effects remain unclear. This study aimed to assess the long-term impact of dapagliflozin on CFR and EAT thickness in T2DM patients. Methods Patients with T2DM and stable CAD were enrolled in the DAPAHEART trial, a single-center, 4-week, randomized (1:1 dapagliflozin 10 mg vs placebo), double-blind, controlled study. At the end of the trial, placebo group patients also transitioned to dapagliflozin. CFR and EAT thickness were measured at baseline, after 4 weeks, and after 4 years using 13N-ammonia PET/CT. Results CFR increased 34.4% after 4 years (from 2.15±0.19 at baseline to 2.85±0.26, p=0.001) with 29.18% reduction in EAT thickness (p=0.03). BMI decreased in all patients (p=0.001), but changes in BMI and EAT thickness were not significantly correlated (R² = 0.0662; p = 0.5038), suggesting a weight-independent effect of dapagliflozin on EAT. Conclusions The 30% CFR improvement seen after 4 weeks of dapagliflozin persisted at 4 years, together with a significant reduction in EAT thickness, possibly explaining CFR improvement. Similar results in the placebo group after treatment, strongly support a causal relationship and underscore the long-term CV benefits of dapagliflozin and its role in reducing CV risk in T2DM patients. Coronary Flow Reserve SGLT2i Dapagliflozin Type 2 Diabetes Coronary Artery Disease Long-Term Coronary Flow Reserve Epicardial Adipose Tissue Figures Figure 1 Figure 2 Figure 3 Introduction Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease associated with a significantly increased risk of cardiovascular (CV) disease, including coronary artery disease (CAD) and heart failure (HF) 1 . Despite advancements in glycemic control therapies, reducing CV morbidity and mortality in T2DM patients remains a critical challenge 2 . Although microvascular complications are closely associated with CV morbidity, and glycemic control effectively reduces microvascular damage, to date, no trial has conclusively demonstrated that lowering HbA1c alone significantly reduces major adverse cardiovascular events (MACE) in patients with established microvascular disease, i.e., in the context of secondary prevention. 3 However, some therapies have shown cardioprotective effects, reducing MACE independently of glycemic control. 4 Sodium-glucose cotransporter-2 inhibitors (SGLT2i) represent a breakthrough in the management of T2DM, with extensive cardiovascular outcome trials (CVOTs) showing reductions in CV mortality, HF hospitalizations, and renal disease progression. 5 – 9 Coronary flow reserve (CFR), a key marker of cardiovascular health, particularly in patients with type 2 diabetes mellitus (T2DM) 10 , is a fundamental indicator of coronary circulation, reflecting the ability of coronary arteries to increase blood flow during stress compared to rest (CFR = myocardial blood flow [MBF] at stress / MBF at rest). 11 In T2DM, CFR is frequently reduced due to microvascular dysfunction, which contributes to a higher risk of ischemic events. 6 , 12 , 13 A potential cause of microvascular dysfunction may be the loss of the cardio protective effect of epicardial adipose tissue (EAT) 14 , 15 . In type 2 diabetes, this distinct brown adipose tissue depot has been reported to undergo morphological and functional alterations shifting toward white adipose tissue characteristics along with increased thickening and inflammation 14 . Increased inflammation of EAT, indicated by the whitening of brown adipose tissue, has been widely documented in the literature 16 – 19 . Chronic inflammation contributes to microvascular dysfunction, which is detectable through a reduction in CFR 20 , 21 . Due to its close anatomical proximity to the heart and its potential to regain its anti-inflammatory molecule secreting activity, thus improving CFR, EAT is now recognized as an important, independent, and modifiable cardiovascular risk factor 22 – 24 . Another potential consequence of microvascular dysfunction is the reduction in myocardial mechano-energetic efficiency (MEEi) 25 , a measure of cardiac performance, which assesses the heart's efficiency in converting metabolic energy into mechanical work 26 . MEEi, which is typically reduced in T2DM, due to cardiac insulin resistance and altered substrate utilization, 26 provides valuable insights into the functional impact of therapeutic interventions on myocardial efficiency. 13 , 27 Preserving or improving MEEi is essential for maintaining cardiac energy efficiency in this high-risk population. In the DAPAHEART trial, a recent single-center, 4-week, randomized, double-blind, controlled study (1:1 dapagliflozin 10 mg vs placebo), we demonstrated that treatment with dapagliflozin induced a 30% increase in CFR in patients with T2DM and stable CAD. 28 , 29 The improvement in CFR was associated with a selective 19% reduction in EAT thickness and glucose uptake, suggesting a restoration of the protective effect of this fat depot. Indeed, the reestablishment of the protective function of EAT may have effects on microvascular dysfunction, potentially accounting for the observed improvements in CRF, as previously mentioned 20 , 21 , 30 . However, whether these benefits are maintained over longer periods remains unexplored. This follow up study aimed to address this knowledge gap by evaluating the long-term effects of dapagliflozin on CFR, EAT and MEEi over a 4-year period, providing insights into its sustained cardioprotective potential. Methods Details of the DAPAHEART study design can be found in the protocol paper 28 . In this 4-year follow up analysis, we aimed to evaluate the effect of dapagliflozin treatment on: coronary flow reserve (CFR), epicardial adipose tissue (EAT) thickness and myocardial mechano-energetic efficiency (MEEi). Ethics and Approvals The study was approved by the local ethics committee of Fondazione Policlinico Universitario Agostino Gemelli IRCCS (study protocol code GIA-DAP-16-005) and registered at EudraCT (No. 2016-003614-27) and ClinicalTrials.gov (NCT 03313752). All participants provided written informed consent prior to enrollment. Trial Design and Participants The DAPAHEART trial was designed as a double-blind, placebo-controlled study with a four-week intervention period. Eligible participants were randomized in a 1:1 ratio to receive either dapagliflozin (10 mg, orally, once daily) or placebo. At the end of 4 weeks, all the patients in the placebo group were switched to dapagliflozin 10 mg treatment. After 4 years, the same cohort of participants was re-evaluated to assess the long-term effects of dapagliflozin. Fig. 1: Trial design. At the 4-year follow up, CFR and EAT thickness were measured using ¹³NH Positron Emission Tomography/Computed Tomography (PET/CT). MEEi was evaluated using transthoracic (TT) echocardiography and was defined as the ratio between the external systolic work, and the amount of total energy generated for each contraction. In particular, MEEi was calculated using the following formula: SBP (systolic blood pressure) × SV (stroke volume)/ SBP × HR (heart rate) = SV/HR; SV was obtained through the transthoracic echocardiogram as the difference between LV end-diastolic and end-systolic volumes, and HR was expressed in seconds (HR/60).). 25 Statistical analysis The sample size estimation and statistical analysis details are outlined in the study design protocol 28 . Data are expressed as mean ± standard error of the mean (SEM) or median with a 95% confidence interval (CI), depending on distribution. Normality of data was evaluated prior to analysis. For within-group comparisons, paired t-tests or their non-parametric equivalents were employed. Between-group differences were analyzed using unpaired t-tests or equivalent non-parametric tests. Additionally, repeated measures analysis was conducted to assess treatment effects and group differences. Results Study population In the 4-week trial a total of 16 patients were included and randomized to receive dapagliflozin (n = 8) or placebo (n = 8). The two groups were homogeneous in terms of baseline characteristics. The follow-up study included 9 patients, since during the follow up period one participant died, three discontinued treatments due to adverse effects, and three were lost to follow up. Detailed demographic and baseline characteristics of each group are summarized in Table 1 . With regard to medications, treatment strategies were adjusted as needed throughout the follow-up period, reflecting a shift towards more modern and effective diabetes treatments: metformin use remained constant, with 7 patients (77%) continuing treatment from baseline through the follow-up period. DPP4i were discontinued entirely, because of the shift to GLP-1 receptor agonists (GLP-1 RA). GLP-1 RAs were introduced in a significantly higher number of patients, from 3 patients (33%) at baseline to 8 patients (88%) at follow-up. Sulfonylureas were completely discontinued in all patients Table. 1 . Table 1 Data are mean ± SEM. HbA1c, glycated hemoglobin; BMI, body mass index Effect of dapagliflozin treatment on coronary flow reserve and epicardial adipose tissue thickness after 4 years We observed a significant increase in CFR across all patients after 4 years (from 2.15 ± 0.19 at baseline to 2.85 ± 0.26 at 4-year follow up, p = 0.001) Fig. 2 A. In particular, at 4-year follow up, the dapagliflozin-treated group (group A) maintained the 30% increase in CFR observed during the initial phase (from 3.44 ± 0.34 at 4 weeks to 3.18 ± 0.44 at 4-year follow up; p = ns between 4 weeks vs 4 years) Fig. 2 B. Group B, the former placebo group, that initiated dapagliflozin after 4 weeks, showed a significant increase in CFR (from 1.96 ± 0.09 at 4 weeks to 2.43 ± 0.15 at 4-year follow up; p = 0.007) Fig. 2 C. Myocardial blood flow (MBF) at rest was significantly reduced by dapagliflozin treatment in all patients (from 1.16 ± 0.06 at baseline to 0.88 ± 0.07 mL/min/g at 4-year follow up; p = 0.008) Fig. 2 D. The dapagliflozin group (group A) maintained the significant reduction of MBF at rest over the 4-year follow up period (from 1.15 ± 0.11 at baseline to 0.81 ± 0.05 at 4 weeks to 0.78 ± 0.082 mL/min/g at 4 years; p = ns between 4 weeks vs 4 years and p = 0.008 between baseline and 4 year follow up) Fig. 2 E. Group B showed a slightly reduction of MBF at rest (from 1.11 ± 0.09 at 4 week to 1 ± 0.11 mL/min/g at 4-year follow up; p = ns) Fig. 2 F. Stress MBF was slightly increased in all patients without reaching statistical significance (from 2.32 ± 0.11 at baseline to 2.38 ± 0.13 mL/min/g at 4 years; p = ns) Fig. 2 G. No significant changes in stress MBF were recorded for group A (2.41 ± 0.2 at baseline to 2.67 ± 0.23 at 4 weeks to 2.38 ± 0.2 mL/min/g at 4 years; p = ns)Fig. 2 H, whereas in the group B we observed a significant increase in stress MBF (from 2.085 ± 0.23 at 4 week to 2.38 ± 0.22 mL/min/g at 4-year follow up; p = 0.03) Fig. 2 I . We observed a significant 29% reduction of EAT thickness in all patients (from 0.62 ± 0.18 at baseline to 0.44 ± 0.11 cm at 4 years; p = 0.03) Fig. 3 A. In group A, the reduction in EAT thickness increased compared to baseline (from 0.68 ± 0.12 at baseline to 0.53 ± 0.07 at 4 weeks to 0.42 ± 0.06 cm at 4 years; p = 0.03) Fig. 3 B. In group B we observed a 19% reduction (from 0.56 ± 0.1 at baseline to 0.56 ± 0.09 at 4 weeks to 0.45 ± 0.07 cm at 4 years; p = 0.04) Fig. 3 C. BMI was significantly reduced (from 28.02 ± 1,1 from baseline to 25.2 ± 0.82 kg/m 2 at 4 years, p = 0.001). Interestingly, no significant correlation was found between BMI reduction and changes in EAT thickness (R 2 = 0.0662; p = 0.5. Data not shown). Of note, in a subgroup of patients we observed that the initiation of GLP-1 RA at 4 weeks did not lead to a significantly greater reduction in EAT compared to those already on it at baseline, suggesting a prominent role of SGLT-2i in this outcome (p = 0.6; data not shown). [ INSERT Fig. 3 HERE ] At baseline, the mean MEEi was 0.323 ml/(sg) −1 , and no significant changes were observed after four years of dapagliflozin treatment, with a final MEEi of 0.322 ml/(sg) −1 (p = 0.94) (data not shown). Discussion The findings from the 4-year follow up of the DAPAHEART trial demonstrate the significant and long lasting cardiovascular benefits of dapagliflozin in patients with T2DM and stable CAD. The main effects of dapagliflozin observed in this study include: 1) approximately 30% sustained improvement in CFR; 2) a sustained, and even progressive, reduction in EAT thickness; 3) a reduction in myocardial resting blood flow, suggesting enhanced myocardial perfusion efficiency; 4)the stabilization of MEEi, maintaining stable cardiac energy expenditure over time; 5) a causal relationship, as evidenced by the outcomes observed in the placebo group that initiated dapagliflozin at the end DAPAHEART trial. The latter finding reinforces the overall data and provides internal validation within the trial design, thereby helping to isolate the effects of dapagliflozin and strengthen the conclusion that the drug is responsible for the observed improvements in CFR and reductions in EAT thickness. These effects are consistent with the mechanisms proposed in the literature supporting the cardioprotective role of SGLT2 inhibitors. The improvement in CFR is particularly significant, as it indicates the myocardial enhanced capacity to increase blood flow during periods of increased demand, such as physical exercise. In patients with T2DM, this improved CFR could translate into greater protection against ischemic events, reducing the risk of coronary complications 20 , 21 , 31 . The reduction in EAT thickness observed in this study is important because EAT alteration has been linked to coronary microvascular dysfunction and inflammation. 32 , 33 By reducing EAT thickness, dapagliflozin likely mitigates the local inflammatory response, thereby improving coronary perfusion and CFR, thus enhancing the myocardial ability to meet increased oxygen demands. 34 Indeed, reduced inflammatory activity in EAT decreases the burden on coronary arteries, allowing for better vasodilation and more efficient blood flow during stress conditions. 35 In addition to the benefits on CFR and EAT, the MEEi was evaluated as a secondary outcome in the DAPAHEART follow up study. MEEi measures the efficiency with which the heart converts metabolic energy into mechanical work. In this study, dapagliflozin helped maintain stable MEEi levels over the 4 years. Although no significant increase was observed, the preservation of MEEi is particularly important in patients with T2DM, in whom cardiac energetic efficiency is frequently impaired as a result of insulin resistance and an increased fatty acid metabolism. 36 In fact, several studies have shown that MEEi progressively declines in parallel with worsening insulin resistance, with higher HOMA-IR quartiles being independently associated with lower MEEi values. 25 , 37 It is also known that the progression of insulin resistance and microvascular damage over time contributes to further deterioration of myocardial function, especially in the absence of optimal glycemic control. Therefore, the preservation of MEEi that we observed in this study represents a relevant outcome, suggesting that dapagliflozin may help maintain efficient cardiac performance over time, potentially contributing to the improved CFR observed. An additional factor contributing to the observed reductions in body weight and HbA1c during follow-up was the initiation of GLP-1 RAs, which are known for their potent weight-lowering properties and beneficial effects on glycated haemoglobin. 38 – 40 This combination of therapies likely enhanced overall metabolic outcomes in this population. Interestingly, we did not observe any significant correlation between BMI reduction and changes in EAT thickness, suggesting that even though EAT expresses the GLP-1 receptor, 41 the main effect is exerted indirectly by SGLT-2 inhibition 42 . The initiation of GLP-1 receptor agonists (GLP-1 RAs) at 4 weeks in a subgroup of patients did not lead to a significantly greater reduction in EAT compared to those already receiving GLP-1 RAs at baseline, suggesting that SGLT-2 inhibitors may have played a predominant role in mediating this effect. Overall, the 4-year follow up of the DAPAHEART trial demonstrates the long-term efficacy of dapagliflozin in improving coronary microvascular function, particularly through a sustained increase in CFR. This increase, together with the reduction in EAT and maintenance of MEEi, underscores the multifaceted cardioprotective effects of dapagliflozin. These findings support the continued use of dapagliflozin as a key therapeutic option for reducing cardiovascular risk in patients with T2DM and stable CAD. Limitation and strengths of the study This study has several strengths that support the importance of the findings. First, patients were closely and consistently monitored throughout the 4-year follow up period. Despite the use of multiple invasive tests, a significant number of the enrolled patients completed the study, underscoring the commitment of both participants and researchers. Additionally, the sophisticated imaging techniques used, namely PET/CT, allowed for accurate and reproducible detailed assessment of myocardial perfusion as well as adipose tissue depots. This enabled the identification of the selective effect of SGLT2i on EAT in just 4 weeks, contributing to a deeper understanding of the rapid cardiovascular benefits of these drugs. However, the study has some limitations. One of the most significant limitations is the relatively small number of patients recruited, which likely contributed to some results trending toward significance but not reaching it. A larger sample size would have provided greater statistical power to detect significance. Unfortunately, the first part of the study (Dapaheart trial) was conducted during the COVID19 pandemic, so a substantial number of potential participants refused to enter the study due to its complexity and the fear of being in a hospital during that period. Lastly, while this study demonstrated a reduction in myocardial blood flow and an increase in CFR, the correlation between these changes and clinical outcomes, such as a reduction in major cardiovascular events, remains to be clarified. A longer follow up period and a larger cohort would help to better evaluate the clinical significance of these findings. Conclusion To conclude, this study underlines the long-term impact of dapagliflozin on coronary health in patients with T2DM and stable CAD. Beyond glycemic control, SGLT2i actively mitigate the metabolic and inflammatory burden imposed by visceral adiposity on the heart. Our findings underscore the pivotal role of SGLT2 in reducing the progression of cardiovascular risk in patients with T2DM and may have important implications for the management of coronary microvascular dysfunction in this population. By preserving CFR, maintaining MEEi and reducing EAT thickness, SGLT2i provide a comprehensive and sustained protective cardiovascular effect. Future studies should investigate longer follow up periods and larger patient cohorts to fully understand the potential of SGLT2i in cardiovascular prevention strategies, as well as its interplay with other therapeutic agents in this population. Abbreviations CAD coronary artery disease EAT epicardial adipose tissue HF heart failure MACE major cardiovascular events PET positron emission tomography SGLT-2i sodium-glucose cotransporter-2 inhibitors T2DM:type 2 diabetes T2DM Type 2 diabetes CV cardiovascular Declarations Ethics approval and consent to participate The study was approved by the local ethics committee (Fondazione Policlinico Universitario Agostino Gemelli IRCCS, study protocol code GIA-DAP-16-005) and registered at eudract.ema.europa.eu (EudraCT No. 2016-003614-27) and ClinicalTrials.gov (NCT 03313752). Written informed consent was obtained from all participants. Consent for publication The corresponding author certifies the accuracy of content, in particular, the names of coauthors and that addresses and affiliations are up to date. The corresponding author certifies that all the co-authors have agreed to all the contents and will notify all the authors when the manuscript is accepted. The corresponding author certifies that all authors have seen and approved the final version of the paper and all are aware of the submission of the paper. All authors consent to publication. Availability of data and materials The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests None of the authors have any competing interests in the manuscript. Funding The submitted project was funded by a pharmaceutical company (AstraZeneca) to cover tracer costs. Authors' contributions F. Cinti, GPS, LL, PI and A. Giaccari designed the trial; A. Guarnieri, LL and MLC described and reviewed PET/CT procedures. LC performed, and DD, FB and F. Crea reviewed, the cardiological procedures. F. Cinti, CM, SG, TM, AS, AA, AP performed and followed up the metabolic procedures. LL and A. Guarnieri performed the PET/CT scans. F. Cinti, CM, A. Guarnieri, LC, LL and GPS were the major contributors in analyzing data and writing the manuscript. All authors have read and approved the final manuscript. Acknowledgements Medical writing/Editorial assistance: we thank Serena Rotunno (Università Cattolica del Sacro Cuore). We would like to acknowledge the contribution of the Multispecialistic Biobank Research Core Facility G-STeP, Fondazione Policlinico Universitario “A. Gemelli” IRCCS (Biobank-FPG) who provided the bioresources. References De Rosa, S. et al. Type 2 Diabetes Mellitus and Cardiovascular Disease: Genetic and Epigenetic Links. Front Endocrinol (Lausanne) 9 , 2 (2018). https://doi.org:10.3389/fendo.2018.00002 Holman, R. R., Sourij, H. & Califf, R. M. Cardiovascular outcome trials of glucose-lowering drugs or strategies in type 2 diabetes. Lancet 383 , 2008-2017 (2014). https://doi.org:10.1016/S0140-6736(14)60794-7 Mahaffey, K. W. et al. Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation 137 , 323-334 (2018). https://doi.org:10.1161/CIRCULATIONAHA.117.032038 Lopaschuk, G. D. & Verma, S. Mechanisms of Cardiovascular Benefits of Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: A State-of-the-Art Review. JACC Basic Transl Sci 5 , 632-644 (2020). https://doi.org:10.1016/j.jacbts.2020.02.004 Cinti, F. et al. The effects of SGLT2i on cardiac metabolism in patients with HFpEF: Fact or fiction? Cardiovasc Diabetol 24 , 208 (2025). https://doi.org:10.1186/s12933-025-02767-9 D'Amario, D. et al. Impact of coronary microvascular dysfunction in heart failure with preserved ejection fraction: a meta-analysis. ESC Heart Fail 11 , 2063-2075 (2024). https://doi.org:10.1002/ehf2.14626 Zelniker, T. A. et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 393 , 31-39 (2019). https://doi.org:10.1016/S0140-6736(18)32590-X Scheen, A. J. [EMPA-REG OUTCOME: Empagliflozin reduces mortality in patients with type 2 diabetes at high cardiovascular risk]. Rev Med Liege 70 , 583-589 (2015). Beernink, J. M. et al. Efficacy of Dapagliflozin by Baseline Diabetes Medications: A Prespecified Analysis From the DAPA-CKD Study. Diabetes Care 46 , 602-607 (2023). https://doi.org:10.2337/dc22-1514 Niewiara, L. et al. Impaired coronary flow reserve in patients with poor type 2 diabetes control: Preliminary results from prospective microvascular dysfunction registry. Cardiol J 31 , 185-192 (2024). https://doi.org:10.5603/CJ.a2022.0100 Galante, D. et al. Fractional flow reserve (FFR) and index of microcirculatory resistance (IMR) relationship in patients with chronic or stabilized acute coronary syndromes. Int J Cardiol 422 , 132978 (2025). https://doi.org:10.1016/j.ijcard.2025.132978 Kato, S. et al. Coronary Flow Reserve by Cardiac Magnetic Resonance Imaging in Patients With Diabetes Mellitus. JACC Cardiovasc Imaging 12 , 2579-2580 (2019). https://doi.org:10.1016/j.jcmg.2019.07.010 Nesti, L. et al. Effect of empagliflozin on left ventricular contractility and peak oxygen uptake in subjects with type 2 diabetes without heart disease: results of the EMPA-HEART trial. Cardiovasc Diabetol 21 , 181 (2022). https://doi.org:10.1186/s12933-022-01618-1 Iacobellis, G. Epicardial adipose tissue in contemporary cardiology. Nat Rev Cardiol 19 , 593-606 (2022). https://doi.org:10.1038/s41569-022-00679-9 Crea, F., Camici, P. G. & Bairey Merz, C. N. Coronary microvascular dysfunction: an update. Eur Heart J 35 , 1101-1111 (2014). https://doi.org:10.1093/eurheartj/eht513 Malavazos, A. E. et al. The density of crown-like structures in epicardial adipose tissue could play a role in cardiovascular diseases. Eat Weight Disord 27 , 2905-2910 (2022). https://doi.org:10.1007/s40519-022-01420-8 Giordano, A. et al. Obese adipocytes show ultrastructural features of stressed cells and die of pyroptosis. J Lipid Res 54 , 2423-2436 (2013). https://doi.org:10.1194/jlr.M038638 Kotzbeck, P. et al. Brown adipose tissue whitening leads to brown adipocyte death and adipose tissue inflammation. J Lipid Res 59 , 784-794 (2018). https://doi.org:10.1194/jlr.M079665 Giordano, A. et al. The Adipose Organ Is a Unitary Structure in Mice and Humans. Biomedicines 10 (2022). https://doi.org:10.3390/biomedicines10092275 Recio-Mayoral, A. et al. Chronic inflammation and coronary microvascular dysfunction in patients without risk factors for coronary artery disease. Eur Heart J 30 , 1837-1843 (2009). https://doi.org:10.1093/eurheartj/ehp205 Taqueti, V. R. & Ridker, P. M. Inflammation, coronary flow reserve, and microvascular dysfunction: moving beyond cardiac syndrome X. JACC Cardiovasc Imaging 6 , 668-671 (2013). https://doi.org:10.1016/j.jcmg.2013.02.005 Iacobellis, G. & Baroni, M. G. Cardiovascular risk reduction throughout GLP-1 receptor agonist and SGLT2 inhibitor modulation of epicardial fat. J Endocrinol Invest 45 , 489-495 (2022). https://doi.org:10.1007/s40618-021-01687-1 Pedicino, D. et al. Epicardial adipose tissue microbial colonization and inflammasome activation in acute coronary syndrome. Int J Cardiol 236 , 95-99 (2017). https://doi.org:10.1016/j.ijcard.2017.02.040 Antoniades, C. et al. Perivascular adipose tissue as a source of therapeutic targets and clinical biomarkers. Eur Heart J (2023). https://doi.org:10.1093/eurheartj/ehad484 Succurro, E. et al. Impaired insulin-stimulated myocardial glucose metabolic rate is associated with reduced estimated myocardial energetic efficiency in subjects with different degrees of glucose tolerance. Cardiovasc Diabetol 22 , 4 (2023). https://doi.org:10.1186/s12933-022-01733-z Vanessa Fiorentino, T. et al. Depressed myocardial mechano-energetic efficiency in subjects with dysglycemia. Diabetes Res Clin Pract 177 , 108883 (2021). https://doi.org:10.1016/j.diabres.2021.108883 Mancusi, C. et al. Effect of diabetes and metabolic syndrome on myocardial mechano-energetic efficiency in hypertensive patients. The Campania Salute Network. J Hum Hypertens 31 , 424 (2017). https://doi.org:10.1038/jhh.2017.3 Sorice, G. P. et al. Effect of Dapagliflozin on Myocardial Insulin Sensitivity and Perfusion: Rationale and Design of The DAPAHEART Trial. Diabetes Ther 12 , 2101-2113 (2021). https://doi.org:10.1007/s13300-021-01083-1 Leccisotti, L. et al. Dapagliflozin improves myocardial flow reserve in patients with type 2 diabetes: the DAPAHEART Trial: a preliminary report. Cardiovasc Diabetol 21 , 173 (2022). https://doi.org:10.1186/s12933-022-01607-4 Cinti, F. et al. Dapagliflozin treatment is associated with a reduction of epicardial adipose tissue thickness and epicardial glucose uptake in human type 2 diabetes. Cardiovasc Diabetol 22 , 349 (2023). https://doi.org:10.1186/s12933-023-02091-0 Sardu, C. et al. Effects of Sodium-Glucose Transporter 2 Inhibitors (SGLT2-I) in Patients With Ischemic Heart Disease (IHD) Treated by Coronary Artery Bypass Grafting via MiECC: Inflammatory Burden, and Clinical Outcomes at 5 Years of Follow-Up. Front Pharmacol 12 , 777083 (2021). https://doi.org:10.3389/fphar.2021.777083 Cherian, S., Lopaschuk, G. D. & Carvalho, E. Cellular cross-talk between epicardial adipose tissue and myocardium in relation to the pathogenesis of cardiovascular disease. Am J Physiol Endocrinol Metab 303 , E937-949 (2012). https://doi.org:10.1152/ajpendo.00061.2012 Conte, M. et al. Inflammation and Cardiovascular Diseases in the Elderly: The Role of Epicardial Adipose Tissue. Front Med (Lausanne) 9 , 844266 (2022). https://doi.org:10.3389/fmed.2022.844266 Duyuler, S. & Turker Duyuler, P. Epicardial adipose tissue in coronary microvascular dysfunction. Int J Obes (Lond) 46 , 1564 (2022). https://doi.org:10.1038/s41366-022-01125-z Iacobellis, G., Corradi, D. & Sharma, A. M. Epicardial adipose tissue: anatomic, biomolecular and clinical relationships with the heart. Nat Clin Pract Cardiovasc Med 2 , 536-543 (2005). https://doi.org:10.1038/ncpcardio0319 Mancusi, C. et al. Effect of diabetes and metabolic syndrome on myocardial mechano-energetic efficiency in hypertensive patients. The Campania Salute Network. J Hum Hypertens 31 , 395-399 (2017). https://doi.org:10.1038/jhh.2016.88 Mancusi, C. et al. Myocardial mechano-energetic efficiency and insulin resistance in non-diabetic members of the Strong Heart Study cohort. Cardiovasc Diabetol 18 , 56 (2019). https://doi.org:10.1186/s12933-019-0862-9 Admani, B., Fahim, M. & Ahmed, H. Semaglutide and weight loss - A concern for diabetics and pharmaceuticals. J Pak Med Assoc 74 , 1204 (2024). https://doi.org:10.47391/JPMA.10705 Tzoulis, P., Batavanis, M. & Baldeweg, S. A Real-World Study of the Effectiveness and Safety of Semaglutide for Weight Loss. Cureus 16 , e59558 (2024). https://doi.org:10.7759/cureus.59558 Swift, C. et al. Real-world glycated haemoglobin changes among type 2 diabetes mellitus patients treated with a maintenance dose of 7 mg or 14 mg of oral semaglutide. Diabetes Obes Metab 26 , 2111-2118 (2024). https://doi.org:10.1111/dom.15516 Malavazos, A. E. et al. Human epicardial adipose tissue expresses glucose-dependent insulinotropic polypeptide, glucagon, and glucagon-like peptide-1 receptors as potential targets of pleiotropic therapies. Eur J Prev Cardiol 30 , 680-693 (2023). https://doi.org:10.1093/eurjpc/zwad050 Morciano, C. et al. SGLT2 inhibition and adipose tissue metabolism: current outlook and perspectives. Cardiovasc Diabetol 23 , 449 (2024). https://doi.org:10.1186/s12933-024-02539-x Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 31 Aug, 2025 Read the published version in Cardiovascular Diabetology → Version 1 posted Editorial decision: Revision requested 22 Jun, 2025 Reviews received at journal 22 Jun, 2025 Reviews received at journal 21 Jun, 2025 Reviews received at journal 18 Jun, 2025 Reviews received at journal 14 Jun, 2025 Reviews received at journal 13 Jun, 2025 Reviewers agreed at journal 05 Jun, 2025 Reviewers agreed at journal 30 May, 2025 Reviewers agreed at journal 30 May, 2025 Reviewers agreed at journal 29 May, 2025 Reviewers agreed at journal 29 May, 2025 Reviewers agreed at journal 29 May, 2025 Reviewers agreed at journal 28 May, 2025 Reviewers agreed at journal 27 May, 2025 Reviewers invited by journal 27 May, 2025 Editor assigned by journal 27 May, 2025 Submission checks completed at journal 27 May, 2025 First submitted to journal 27 May, 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. 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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-6758884","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":467706881,"identity":"e54591cc-4ed1-453a-8718-8d6b7692693e","order_by":0,"name":"Francesca Cinti","email":"","orcid":"","institution":"Centro Malattie Endocrine e Metaboliche, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS and Università Cattolica del Sacro Cuore","correspondingAuthor":false,"prefix":"","firstName":"Francesca","middleName":"","lastName":"Cinti","suffix":""},{"id":467706882,"identity":"08f13763-b706-4292-b856-cbdaf605fafc","order_by":1,"name":"Cassandra Morciano","email":"","orcid":"","institution":"Centro Malattie Endocrine e Metaboliche, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS and Università Cattolica del Sacro Cuore","correspondingAuthor":false,"prefix":"","firstName":"Cassandra","middleName":"","lastName":"Morciano","suffix":""},{"id":467706883,"identity":"c5c438b4-2ba9-4cd2-88e3-a52b6b5638ca","order_by":2,"name":"Andrea Guarneri","email":"","orcid":"","institution":"Unità di Medicina Nucleare, Fondazione Policlinico Universitario A. Gemelli IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Andrea","middleName":"","lastName":"Guarneri","suffix":""},{"id":467706884,"identity":"625429c9-0e24-446d-a8d9-2a3780c63b52","order_by":3,"name":"Luigi Cappannoli","email":"","orcid":"","institution":"UOC di Cardiologia, Dipartimento di Scienze Cardiovascolari, Fondazione Policlinico Universitario A. Gemelli IRCCS, and Università Cattolica del Sacro Cuore","correspondingAuthor":false,"prefix":"","firstName":"Luigi","middleName":"","lastName":"Cappannoli","suffix":""},{"id":467706885,"identity":"1b3c6057-79dc-498f-b441-b2ea51dec689","order_by":4,"name":"Gian Pio Sorice","email":"","orcid":"","institution":"Centro Malattie Endocrine e Metaboliche, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS and Università Cattolica del Sacro Cuore","correspondingAuthor":false,"prefix":"","firstName":"Gian","middleName":"Pio","lastName":"Sorice","suffix":""},{"id":467706886,"identity":"44956b5b-fdbc-4524-8a00-492425a9280b","order_by":5,"name":"Shawn Gugliandolo","email":"","orcid":"","institution":"Centro Malattie Endocrine e Metaboliche, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS and Università Cattolica del Sacro Cuore","correspondingAuthor":false,"prefix":"","firstName":"Shawn","middleName":"","lastName":"Gugliandolo","suffix":""},{"id":467706887,"identity":"2f19bbca-d2ce-491e-acd1-9697b87a1390","order_by":6,"name":"Umberto Capece","email":"","orcid":"","institution":"Centro Malattie Endocrine e Metaboliche, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. 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Gemelli IRCCS and Università Cattolica del Sacro Cuore","correspondingAuthor":false,"prefix":"","firstName":"Teresa","middleName":"","lastName":"Mezza","suffix":""},{"id":467706891,"identity":"911b5a9d-d70a-40ba-9604-75c6cac3e2d4","order_by":10,"name":"Patricia Iozzo","email":"","orcid":"","institution":"Consiglio Nazionale delle Ricerche (CNR)","correspondingAuthor":false,"prefix":"","firstName":"Patricia","middleName":"","lastName":"Iozzo","suffix":""},{"id":467706892,"identity":"4230201b-1b51-4aa4-8805-243162455bcb","order_by":11,"name":"Alfredo Pontecorvi","email":"","orcid":"","institution":"Centro Malattie Endocrine e Metaboliche, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS and Università Cattolica del Sacro Cuore","correspondingAuthor":false,"prefix":"","firstName":"Alfredo","middleName":"","lastName":"Pontecorvi","suffix":""},{"id":467706893,"identity":"454053ea-c851-4e7d-9e4c-37d4e93d9f13","order_by":12,"name":"Maria Lucia Calcagni","email":"","orcid":"","institution":"Sezione di Medicina Nucleare, Dipartimento di Scienze Radiologiche ed Ematologia, Università Cattolica del Sacro Cuore","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Lucia","lastName":"Calcagni","suffix":""},{"id":467706894,"identity":"cfe5a8c5-8b5d-4f34-942f-a4ae08493726","order_by":13,"name":"Francesco Burzotta","email":"","orcid":"","institution":"UOC di Cardiologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, and Università Cattolica del Sacro Cuore","correspondingAuthor":false,"prefix":"","firstName":"Francesco","middleName":"","lastName":"Burzotta","suffix":""},{"id":467706895,"identity":"22c7b514-d0ca-4f30-bcec-fd0bf0f4a502","order_by":14,"name":"Domenico D’Amario","email":"","orcid":"","institution":"Università del Piemonte Orientale, Dipartimento di Medicina Traslazionale","correspondingAuthor":false,"prefix":"","firstName":"Domenico","middleName":"","lastName":"D’Amario","suffix":""},{"id":467706896,"identity":"5991125b-621b-4015-92d6-f8f2e8d62990","order_by":15,"name":"Filippo Crea","email":"","orcid":"","institution":"UOC di Cardiologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, and Università Cattolica del Sacro Cuore","correspondingAuthor":false,"prefix":"","firstName":"Filippo","middleName":"","lastName":"Crea","suffix":""},{"id":467706897,"identity":"9dd76627-c363-4dd6-803d-f864048bb558","order_by":16,"name":"Lucia Leccisotti","email":"","orcid":"","institution":"Sezione di Medicina Nucleare, Dipartimento di Scienze Radiologiche ed Ematologia, Università Cattolica del Sacro Cuore","correspondingAuthor":false,"prefix":"","firstName":"Lucia","middleName":"","lastName":"Leccisotti","suffix":""},{"id":467706898,"identity":"85a46e51-2bf5-4857-87cb-55ad4e5991c5","order_by":17,"name":"Andrea Giaccari","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDUlEQVRIiWNgGAWjYHACAzDJBuFIyDEwMDYgixDWYgzRkmDAwIZbjwEKLxFiBVALLmv4Zzdv+/ChhsGuj/3www8/91ikb7jd3Pjh548/DHzyDVi1SNw5VjxzxjGG5DaeNGPJnmcSuRvuHGyW7MHnsBs5xsw8bAzJbAw5bAw8B4BabiS2MfDg0SIP0vLnH1AL/xs2xj8HJNINgFoY/+DRYgDSwtjGYMcmkcPGDLQlAaSFGZ8thjfSihl7+yQS2CSeGUvLHJAwnHkjsVlaJs2Yh40tAasWuRvJmxl+fLOxl+9PfvjxzYE6eb4b6UCGjZycfPMBHP6HBBw0OpAADz71IGBPSMEoGAWjYBSMYAAA5rNT48qDizYAAAAASUVORK5CYII=","orcid":"","institution":"Centro Malattie Endocrine e Metaboliche, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS and Università Cattolica del Sacro Cuore","correspondingAuthor":true,"prefix":"","firstName":"Andrea","middleName":"","lastName":"Giaccari","suffix":""}],"badges":[],"createdAt":"2025-05-27 11:23:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6758884/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6758884/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12933-025-02912-4","type":"published","date":"2025-08-31T15:57:23+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":84199460,"identity":"c0ce35fb-6aef-4ed0-9b10-d15ef0129b51","added_by":"auto","created_at":"2025-06-09 08:15:54","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":121089,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTrial design\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6758884/v1/3b03e284f9a9a8d2fcfe609b.png"},{"id":84198175,"identity":"7a920118-bc71-4378-b237-02be7a0ebc2d","added_by":"auto","created_at":"2025-06-09 08:07:54","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":66811,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEffect of dapagliflozin treatment on coronary flow reserve (CFR): \u003c/strong\u003egroup A included subjects treated with dapagliflozin in the initial phase of the DAPAHEART trial (Group A); group B included subjects initially assigned to placebo treatment and subsequently transitioned to dapagliflozin therapy immediately after the DAPAHEART trial conclusion (Group B). Overall results are presented as Group A+B.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6758884/v1/cae0c424858f74af1a49d812.png"},{"id":84198181,"identity":"468976cc-42d1-48fb-b6f2-41aa4cb823cf","added_by":"auto","created_at":"2025-06-09 08:07:54","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":64880,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEffect of dapagliflozin treatment on epicardial adipose tissue thickness:\u003c/strong\u003e group A included subjects treated with dapagliflozin in the initial phase of the DAPAHEART trial (Group A); group B included subjects initially assigned to placebo treatment and subsequently transitioned to dapagliflozin therapy immediately after the DAPAHEART trial conclusion (Group B). Overall results are presented as Group A+B.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6758884/v1/b5f10defde3d2a0c8384a720.png"},{"id":90344870,"identity":"fb8a6bf7-66a8-49b5-b755-0443cfa8939d","added_by":"auto","created_at":"2025-09-01 16:06:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1185507,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6758884/v1/4a25525a-d038-4e14-883f-e29644454098.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Coronary Flow Reserve increase after Dapagliflozin Treatment in patients with type 2 diabetes is maintained after 4 years: a 4-Year DAPAHEART Follow-up Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eType 2 diabetes mellitus (T2DM) is a chronic metabolic disease associated with a significantly increased risk of cardiovascular (CV) disease, including coronary artery disease (CAD) and heart failure (HF)\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Despite advancements in glycemic control therapies, reducing CV morbidity and mortality in T2DM patients remains a critical challenge\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Although microvascular complications are closely associated with CV morbidity, and glycemic control effectively reduces microvascular damage, to date, no trial has conclusively demonstrated that lowering HbA1c alone significantly reduces major adverse cardiovascular events (MACE) in patients with established microvascular disease, i.e., in the context of secondary prevention. \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e However, some therapies have shown cardioprotective effects, reducing MACE independently of glycemic control.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Sodium-glucose cotransporter-2 inhibitors (SGLT2i) represent a breakthrough in the management of T2DM, with extensive cardiovascular outcome trials (CVOTs) showing reductions in CV mortality, HF hospitalizations, and renal disease progression.\u003csup\u003e\u003cspan additionalcitationids=\"CR6 CR7 CR8\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eCoronary flow reserve (CFR), a key marker of cardiovascular health, particularly in patients with type 2 diabetes mellitus (T2DM) \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, is a fundamental indicator of coronary circulation, reflecting the ability of coronary arteries to increase blood flow during stress compared to rest (CFR\u0026thinsp;=\u0026thinsp;myocardial blood flow [MBF] at stress / MBF at rest). \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e In T2DM, CFR is frequently reduced due to microvascular dysfunction, which contributes to a higher risk of ischemic events.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e A potential cause of microvascular dysfunction may be the loss of the cardio protective effect of epicardial adipose tissue (EAT)\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. In type 2 diabetes, this distinct brown adipose tissue depot has been reported to undergo morphological and functional alterations shifting toward white adipose tissue characteristics along with increased thickening and inflammation\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Increased inflammation of EAT, indicated by the whitening of brown adipose tissue, has been widely documented in the literature\u003csup\u003e\u003cspan additionalcitationids=\"CR17 CR18\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Chronic inflammation contributes to microvascular dysfunction, which is detectable through a reduction in CFR\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Due to its close anatomical proximity to the heart and its potential to regain its anti-inflammatory molecule secreting activity, thus improving CFR, EAT is now recognized as an important, independent, and modifiable cardiovascular risk factor\u003csup\u003e\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAnother potential consequence of microvascular dysfunction is the reduction in myocardial mechano-energetic efficiency (MEEi)\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e, a measure of cardiac performance, which assesses the heart's efficiency in converting metabolic energy into mechanical work\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. MEEi, which is typically reduced in T2DM, due to cardiac insulin resistance and altered substrate utilization,\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e provides valuable insights into the functional impact of therapeutic interventions on myocardial efficiency.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e Preserving or improving MEEi is essential for maintaining cardiac energy efficiency in this high-risk population.\u003c/p\u003e \u003cp\u003eIn the DAPAHEART trial, a recent single-center, 4-week, randomized, double-blind, controlled study (1:1 dapagliflozin 10 mg vs placebo), we demonstrated that treatment with dapagliflozin induced a 30% increase in CFR in patients with T2DM and stable CAD.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e The improvement in CFR was associated with a selective 19% reduction in EAT thickness and glucose uptake, suggesting a restoration of the protective effect of this fat depot. Indeed, the reestablishment of the protective function of EAT may have effects on microvascular dysfunction, potentially accounting for the observed improvements in CRF, as previously mentioned \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHowever, whether these benefits are maintained over longer periods remains unexplored. This follow up study aimed to address this knowledge gap by evaluating the long-term effects of dapagliflozin on CFR, EAT and MEEi over a 4-year period, providing insights into its sustained cardioprotective potential.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eDetails of the DAPAHEART study design can be found in the protocol paper\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. In this 4-year follow up analysis, we aimed to evaluate the effect of dapagliflozin treatment on: coronary flow reserve (CFR), epicardial adipose tissue (EAT) thickness and myocardial mechano-energetic efficiency (MEEi).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eEthics and Approvals\u003c/h2\u003e \u003cp\u003e The study was approved by the local ethics committee of Fondazione Policlinico Universitario Agostino Gemelli IRCCS (study protocol code GIA-DAP-16-005) and registered at EudraCT (No. 2016-003614-27) and ClinicalTrials.gov (NCT 03313752). All participants provided written informed consent prior to enrollment.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTrial Design and Participants\u003c/h3\u003e\n\u003cp\u003eThe DAPAHEART trial was designed as a double-blind, placebo-controlled study with a four-week intervention period. Eligible participants were randomized in a 1:1 ratio to receive either dapagliflozin (10 mg, orally, once daily) or placebo. At the end of 4 weeks, all the patients in the placebo group were switched to dapagliflozin 10 mg treatment. After 4 years, the same cohort of participants was re-evaluated to assess the long-term effects of dapagliflozin.\u003cb\u003eFig.\u0026nbsp;1: Trial design.\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAt the 4-year follow up, CFR and EAT thickness were measured using \u0026sup1;\u0026sup3;NH Positron Emission Tomography/Computed Tomography (PET/CT). MEEi was evaluated using transthoracic (TT) echocardiography and was defined as the ratio between the external systolic work, and the amount of total energy generated for each contraction. In particular, MEEi was calculated using the following formula: SBP (systolic blood pressure) \u0026times; SV (stroke volume)/ SBP \u0026times; HR (heart rate)\u0026thinsp;=\u0026thinsp;SV/HR; SV was obtained through the transthoracic echocardiogram as the difference between LV end-diastolic and end-systolic volumes, and HR was expressed in seconds (HR/60).).\u003csup\u003e25\u003c/sup\u003e\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe sample size estimation and statistical analysis details are outlined in the study design protocol\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. Data are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard error of the mean (SEM) or median with a 95% confidence interval (CI), depending on distribution. Normality of data was evaluated prior to analysis. For within-group comparisons, paired t-tests or their non-parametric equivalents were employed. Between-group differences were analyzed using unpaired t-tests or equivalent non-parametric tests. Additionally, repeated measures analysis was conducted to assess treatment effects and group differences.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eIn the 4-week trial a total of 16 patients were included and randomized to receive dapagliflozin (n\u0026thinsp;=\u0026thinsp;8) or placebo (n\u0026thinsp;=\u0026thinsp;8). The two groups were homogeneous in terms of baseline characteristics. The follow-up study included 9 patients, since during the follow up period one participant died, three discontinued treatments due to adverse effects, and three were lost to follow up. Detailed demographic and baseline characteristics of each group are summarized in \u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e. With regard to medications, treatment strategies were adjusted as needed throughout the follow-up period, reflecting a shift towards more modern and effective diabetes treatments: metformin use remained constant, with 7 patients (77%) continuing treatment from baseline through the follow-up period. DPP4i were discontinued entirely, because of the shift to GLP-1 receptor agonists (GLP-1 RA). GLP-1 RAs were introduced in a significantly higher number of patients, from 3 patients (33%) at baseline to 8 patients (88%) at follow-up. Sulfonylureas were completely discontinued in all patients \u003cb\u003eTable. 1\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eTable\u0026nbsp;1\u003c/strong\u003e \u003cp\u003eData are mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SEM. HbA1c, glycated hemoglobin; BMI, body mass index\u003c/p\u003e \u003c/p\u003e\u003cp\u003e\u003cimg 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WOptTQiCAQcDHPbDJcyis+9ZyWJFMGvmdFnHpsHqVatg2ZJFvpoeCZ25HDlzIUvWrHjz+jUOHzqA06dPybay5cqJPNFJ5UJ69OqDLdt2Yt2GzdigZG/pilVYuGQZ6tZtoIIeZ4wfN0YFb2uVc5hGtm3ash2z5s6T5nn/6gJl3LTee5v6TCekVu26Uvc2bdmG4cNHSV/NDx8/SJP8iRPH/thmyBCBEhrK5J27t5Erd17RkcazD6PkldntcOr5scnbP+csSdIkcFEBtLubO3bt3IZLly6iU9duEnSzFWjQwP4YMXwoyleoJDpvzrz5mDl7rgzSiREjBiJHjixOKfu5MyPPLCZPz4D8vgpUUqVMhThx4pi6Kqlr5eDIM2fPSj1gppx14uPHj8idJw+WrViJRUq+uSxeuhxz5y/A5KkzRL7/1NYh7VhqNL8IDS6bUWhIL1+65NNcHCdOXFEcHDUbQSm8atVqoJwyoB6eHnBRkbApqxJatq9ftwahQodCfRUNz5o7H2nSpsXnzw54+vSxUn5JES16dGnacVTrihUrjooVK6Fw4SISUXt6eCpjHHxVmM0/yZMnl6Yl9jNzU+coVaq0nDNf/gL4rK6XmVadyQl50Dgbzd6Uc/YB42hWDggjHJ17WRln9l1kc585PDZGrFgoUbK0fJ81a6YY/qTJkiu5KiiyTOOcJGky2c5BZ8VLlEDlKlWku8ba1askm8MBGcz03GOmR8FArFatWuKwOqj6wQnagwIdRvbDbNW8CZYsXogiRYuhR58+0p+T/e9ozG2V0ffbhKr5faDzyEwz+zeGDWeaJoqLpaWVtLps3rgRmTJnRloV7FMX+yVe3PgqeI4srT/Tpk5B1arVkF/pOAYcDx4+kFanYSrYaNO2NfLkzaeCjkzifLLfZg4lk5QhDiLj4Eg6tnQ0Gbg4Ozni4/sPsI4YUZrILbyva9/ePXiogq/06dPLdwZR7OLx8tUraQXiZ+r6KEr+ZkybJq1dtBF/qq7VNUej+UnoXJFFC+bL9BAF8+dB/bq1xBgxQi5dpqxSNFGUYssincM53UqWTBnRpWN7cdbEsQwVRiJWTh1UomghZM+aBZUqlJXR4TFjxkSK5CmUk5cClSpXkXMxgs6VPStyZs+CfLlzSPPMkcOHlILyk1XxTsoYH8wzOPwki9k6c/iGHo7gLVuuvOzTrWtnOR8XTrXRoG5tnDt7RmdyQhh0DC0iRMDoMeOw78Ah7D94WJYjx06gY+cusk+qVKmwfuNmtG7bTvod+yWUkic6gjTANLBsqqxUqbJ3f7Yv8lrUxk2bSaDG6a+KFMovzeCcAmjXzh3Sb43Nl9zOOkaWL1uCZk2aoLKqN92VrNLpDKohZh+5Xbt2YsK4sTLVC6c46tmjK+xsbaUZM72qBz5Nq5rfDjr9HMVPXbR65QpMkNk3OHDrtMjCq1cvpa96eIvvW3Qozwwg4idIgMmTxkvg3rFzVwkouC9ljBlITvN25fJVnDlzCuPHjsaYUSMk85glWzbZz83NFNzfvXtLpsmidrW0skaChAlx6tRJmYHj2tWrGDxwAHp27yrHJFMBFP/SsSxbtjzev32LYUMHS9B05/YdOc/ChfOkiwizp9z3T0Q7lhrNT/HVOzqFjEbk9BEcdECFw8EBCxYtRToVlUaysZHRiVmyZJFpfTi/ZdHiJcTZpMFi35uYsWKhWo2aku2hAuIIR84LOGXadGTMlFmaVagc+w8YJEqQ80jyfG9URF6mbFmJlFmOpVKCJHQY5bCGMU06zcidhDWmuwjF9aGlecgygnezkTLCYb0dU6MfEieQHjZiJLr36CWT/tLR5TltP9qKk5s5S2bJbGpCFuw7xoFl2XPkQrbsOWXJkTM3EiZKJNspg1myZkO8+An8NYZ0+jhgLH+BgvKdfeIKFi4kMsn9ub2GqgscgZs9Rw6ROfbxZf9KjsydO3++ZCaZxeneszfKlS8vsyasWL4Uz549Qzclr2nTppOyTKdXDib/8ovP5ZicTnEOsmTF9JmzJft04vgxzJw+DUePHFHnKi39pdOlS4cv/mS6NL8BSha9lA66pBw/DsIZpQKeA/v2oXCBvChbugQ+2dtj8bIVyJo9h79NyZSRyJFtpGWJstO6TVvpJ0m9zCVRosTo1r27ZLML5MstATUHBVWtVh0RlNMZP358KTdJkqSSWV++dKlMZUVdSqe0W4+eojt5XKUK5eR81J3U4WlVcMRz8Phiyh6wmZ0JAs51XLhgXqxbswbjxk9C/foNRf//qahA0lQN/cPRyRUOTk5BjgI1IQOKTBSbiOKs2H128F4bcuBUFPaf7H3VCyoUZjoYQRvKjJ850S0zmXT4qMjoRDp8/ozYceJIvyAa1I8fP8iAGTqEnDONU6B4eLhLGTwHy3mrIlseSweQUxbFjBFDskhUUiyDziZHIrJc7s+O5zxPNBWZR44SxXuf1/LMjH1YNgdNMHPKjBH7DnEdjTeXN+qczjynet6MnnltbMbhOUMSVJC8t9GiRFI60QXO6llpnWiSTcoY5YfyHzN2LITx0wwuqP3YF5mGsnmTxti+fasMWGPfRgZg5n3gKF9s0razs5VsEAOjWDFjSbOieb1i/zo2edJXjBolqpLxqHj18oU0q5vqUCSTzL9+LfJL2WbzpLm5C8q5Qhq8Pxbhw4l+t3dwgqtb0LPA/xbUTcwy8gUOlJ8NGzdLkPFeBfq8Vrb4cD2ff2BQR7I/JUdlszuTIRssg5/Z1O3q6iK6MW6ceKL3P9l/klflch/jOqh72SedC4+jHuf1cA5N1gs6lJQxBwdH6XfJ7QaUQep/W1s70e1Ro0VV1x9L5M9cVn9XmKiIHtXG+9s3tGOp+WkoMiHZsRTHy0w5ECoFGki/1YlKxOirxemJVGWS45kN4b6sW6JovOsY9zE3tAbm5fA4Rux8faOgjqWx5Xojy8Lr43nMy+NIdXpJHPVoXKfxW3j9fh3GQM8ZguCd0o6l/1A+KCfmsmcO7xMnIOd0WhzowOwgnb/+AwejW/ce/hp/X/XLW+68/Mid+T6G7PIVqjyfIfNSt9Q6ElC98nsuZuNDoowb8Dn+7o4lnUCOxq5ZrQqqVq+O4SNGiRwZzzGgZ+0XQ78ZutgckR2Wx9/uLdvcl/Ji3mfTkB+/5/TRnSJT3m8147nUZ64zx3xfqUfc5w8hIMfSZDU0Gk2QoQLhpMvmC5WBX+VEuN7Yh8dRAfGzsS//UlGZ7+Mf5uWYFKHZfizDe72BcR7z8uR4T9+RsPFb/FNmgZ5To1HQqTPkwz9oMJmp5JujOG+fWiOT7XMyaE7X4h++6pcq169TScz3MWSX18DvhsxL3fLex7wemOP3XFrGf3/opPG1nHxhQ4H8heT5mz/HgJ61Xwz95p/e9qWXKRdqnZxDfTbHOK/fc/roTpEp02sepY74cy7zfQ1Z/tMJNGPpwIylIzOW3is0GgVFJmrkSFLB7exDXsZSE7KggmTGMnoUGzg6O8PJWWcsgwrvE5v1zp49I11C+HacbNmzSxPh32JE/yao25mxpH7/xIylq2ne3d8JZgnpVPINZuyzy1ksAnFjNP9HOJdyjGg/2RTu4uYOFwqW93eNhlBkIlpbisJh06BG87dDYxZJyTybBn/H5sHfHfYH5j3kYDO+Po+ZTs3vB52BcCqIsrayhJOradTz7wibjzni2035J0HNUGqCHz4Hm4imgaLmBOpYcpP5ZMoajQFHiSrx8beZSqP5G+HcedSHgahMjeaPh5pdggAt65ofYMiKXwJ1LJ1d3OAozT7eKzQaBUXGJpIVQqt/9o5O3ms1mr8XTosTJZI1nJROlFYcrRQ1fyH0BsKHM2WhHJxd4Obmqe2/JkDYRShq5Ije376hR4VrfhqKTEgeFa4JWVBB6lHhmpAAdfvvPipc8/ugR4VrNBqNRqPRaP6vaMdSo9FoNBqNRhMsaMdSo9FoNBqNRhMsaMdSo9FoNBqNRhMsaMdSo9FoNBqNRhMsaMdSo9FoNBqNRhMsaMdSo9FoNBqNRhMsBO5YhgLChQuP0KHDeK/wTdiwYREmTFjvb6bX+3BdUODcWCybS2DzZLG88OEDvoZfgeczlRlanT+cXLc5/K7n7tL8Kt9k2yRb/BvUehE438r9Vi9+HBsa+/on59zGv8YSlPI0IRfKniHXlKnA5Jrb/C6UXx77zzCrX6pM/2TbP4xr9ruvuR0wFl0P/nzoM4QPb2GSPW+5DcyuhwoV+tv+3nJlLgem8kzyY9QD8/LChg33bbv6yzL8w3R80HT3n0qgv8zRwQF1a9fAmtUr5SYa8Gby/Zw9unXF6FHD5UZZWFhgyeJFaN60Mb5+9frBAwwFFxcXVK9aCVWrVMDnz/bf3WR+t7aOiCuXL6Nc6ZJYsXypnOOfwnN7eHhg1szpqF6lEtq2bonnz5/JbyA8x+ZNGzFq5PC/+sFr/n/wVWgbN65HhbKlUbpkcXRo3wa3b98KUNEEldCqSq1dswolixVBvjw5MXBAPzioOmrIrl8o6xEiWOLlyxeoVaMapk2d7FOPqfi2bd2CIgXzo6yqX1yKFy2MKZMmyNs3Aqu/mpBJmLBhsG/vHlQqXxZFCxdE08YN8fDB/e/kmrLj7u6OenVro0De3ChcIJ9pKZgPObNnxvhxY2WfX5Uxvlpz964dUrcKqvI7dWyPDx8+BFq/WA8+2n5EsyaNMGhgf1UPwsr5WR+OHz+GYkUKoUypEj71YMigAfjy5YuuB38otN2f7GzRt3dPkbsiatmq9B3x75lynaeHO2ZOn4piSrapX6dNnSK+Asvi8v7dW3Tp1EHKo4zs379PjuNCmbxy+SKqKZ+iUP68qFe7Ju7fv+/LbyLUu9evXUXF8mVw5Mjh77b/LQTqOXmqivVAKY6PHz989zC+qn9Pnz3Bq5cv5Ttv/Lt379TNvKe+mTKCESJEkBupDpZ9DHgzL128gFs3b+Dm9Rvq8yVfSoGRw3tV1tTJE9GiWWOcPXsGtra2310DvxvnoUMYkIE1h+c5cvgQNm7YgEFDhsLS0hLTpkyWsnj8mzevsWrlCpQsVfofOwKakAcjXsrXIOX0VapSFb379JG3WfTq0Q12dnaBBisBvgJLEV7J9yYV8AwZNBAVK1dW5fbF3t27MXhAf1F+39UNdR5nZ2csWbQAtWtWx8ED+6VOcT9Z1L979+4hUeLE6NuvP7r36ClllihZSh2t3xGs8Q119plTp9BTyXHe/PnRf8BAWFlZKeeykQQu5rqSskNdWqdOPbTv2Alt23dAuw4d0ap1Wzg5OcHN1VVtD9igBloPlL4/cuQQunftjKJFi6Fv/wHKUF9Dt86dRN791i/Kuoe7B9atXS3GfuuWzXjz+rWPTeL+jx89QpQokdGnbz+felBZ1V3Nn00f5VSeOnUS3br3RJWq1dBFBSC7d+7015njulmzZmL2rBlo3LQZOnbqgjnq+7QpU0SWPT090alTe9y9e1fJRz8UK14crVs0x/Fjx2Gp6sF95Sc1VUFLokSJMHDwEJG7ls2aKH/ijY9Mch1lf8SIYThz+hSc/+K3GgbqWPIn86b49+NpmPhKP/OKzPfp0sFjpEdncMeO7bh14wbCqOONMviX0ewaZl5Kl0ERpRy2bd0sD87Yh+UsX74Uq1etRLXqNZEmTVp4qTLN4Xm/qGMunD+Pneo8R48ewadPn37oDPIcVETFS5RA/oKF0KBREzx89FA5zx/l2FkzpiNzlszImzcfPFT5Gs3P4OX1BadPnkD69BnQqXMXlCtfCT169Ia9vT2ePX0iSsocyiMDowP796Nzh3by3dTt41udo6yz9WDD+nWoVqMGevTsg7r1GmDs+AnYs2e3chDvSlOPOXwF4dMnT7Br1060adseefLlk1aGb3wVmc+VKzeqV62s6lkNVK1WQ8l+Np96qNEQBvpsYZo7exZKlCiJocNGoELFShg5eiySJEuGZ8+eSiBjDuW8arVqaNioMRo0bISmzZor2cqC+PHio3adumoPL1/BC2WOtuPixQto2byJsgce3nXlmyxyHzc3N6xX9aBAwcIYoAx4jZq1MHXadFy6dAHnz5/7zmlgGW/fvcHWzZtQXdmS8hUqSh01vFeW+f79e2TImAk1qleVesAlV+48cqwOsP482D3v5k0mrC5g2IiRSlfWR6/efVFdycrChfPF1zCHz/ndu7fYpfyI9h07o2279mjeoiX69OuHlSuXSTb82tUruKecylFK5mvVroMBAweLc7l40XyRpd1Kz8aMGQujxoyToGTy1Glwc3fD9m1bJRgibCrn+d1c3ZApc+bvruNvIlDH0oD9ARid+l2k4nnvQ2gA2TQ3fNgQ9OvdC8OHDpbm7kWLFvg4fDzmxfPnuHDuPCpXroLSZctIU8Sjhw999uENr16jJnbu2SeRLptg/CohV1cX9OrVA7VrVce4MaPRvm1rNGpYT0UUdwJ1LlmKrZ2tXAczPYxUuT8N8blzZ5Viu6gi63ZSvrtSYoGVpdH4hXKVKHESvHz5Eo8fP1aG0FUZvYvSFBcjRkxfzh1lmvWF2fh379/i1csX8tnW9iM8lFIyjCrrFRUfWw8KFy6i5NZdMj/JU6RUQZob7ty5rYI8384gZTtFypRYuXotmiklGV7VYfM6xDpGGf/w8YM4njWrV8PYMSNV3fgo59NoDEKrQJ9ByK3bt1C6TFlxMpmJoW5cv2GTCsLzi670C51AV1dX+evo6Ih5c2YjV57cSJsu3XdGldsp+3TyXr54IefjwvqjFL7sQwf38+fP0pRYuEgRSTbwuISJEktfyxvXr33nCPI8cePGw6KlK9ClWw9EsLT0XQ9UGc7OTpLt7NKlm9SDwYMG4NXrV1KXNX8eTExduXQJkaNEQTola9SVTHalS58e9+/fVTL2zpeO43Om/0G/IF++/CILlNs0adPJvgycLlw4j/jx4yNZ8mRwUDJHmWR5t27dlH3OnT2LvCp4ZwsoZTJ69BiIFSs2Ll++KLqYyYPjx49gzaqV6NtvAGwi2eALA5y/lB9akDChw0gUuWL5MmkiNhZmE+kgsm+BATMtz54+RRJlWDdt2YbDR0+gSdPmGDt6lDw4PkAue/fshtdXL2TJmhX58xcUBcFo0/xhJ02aDJEiRZIH7FdZUKEtXrQIx48exYaNm7Fn/0EcPHQUYZTimTh+/Hf7m0MVRUVDg84I+bn6DTS6bGqcPHGCut5muHr1Mpo0bCD9RdmPwr/UuUbjH1QizMgkTpIYxYsWkj5bXTp3RLcePdW6JKLgCGXdTRnoSRPGi5wtWrAAt+/cQYd2bdC6ZXOlyC4ouTMFNQykXFxcReFFjhxF5JuLtbU14ill56q2+SfzrCd0ZGn0zbezPF7nG2U8JaK2CI/UaVJL95AObdtI3dDOpcaAOpN62NXVTVp7Gjaoh9Ili0n/yRnTp4rzF5i8iNN34wYOHjiAatVqfieLrBNzZs9CC1UPpk2ZhMePHqNLp45o1aIZDh86iHDqeNO+kEDq82cHRFFOg1EOjXbChInk+vyrByYH8atcJ/v/G8i5leP5QTmzu3bugLsK2OiIHDp4UOokHQbtXP6JhFJOop0kxCxVQE+Z4BIndlxYWdOncJNnbw6dRQYhkWxsZF8vr68iY8xCuji7SNBjocqysIiAr0wOqH3ixYsvCQMXpZfZWho5cmSpBzyecsNuRp4eJn1PWRo3Zgw6dOwkfg/1L1t9/1Z+aD3CKuO2ZdNGdO7YXvq1cOnWpRN6dOsiAxKoNAzYfJEmbVo0bd4C1hEjSoWvXrMmbNQNZ1M1HTTe0G3bt6F06bLi4CVNmlSau9euXiWG03jgfMi+m+5MhFYPjH3Vdu7YJinnHDlzy8OMHiMGJkyaLE0uhvH2D5ZZrFhxHD1yRPq9TZ44XvqV0cBSkNhcM3XyZDRq0lT6ZbD/JaNobWg1QYFywsDpk90n6adDRVKvXn1s2rBeIl/DUFEOLVR0271nLyxeukzVmeZIlSoVZs+Zi/mLFiN7zhxSVwxYK1g3fBtOKkzvjwHge38TXMeymMFZu34jRowcjSFDh2PqtBk4fuwo7t2746teazRUy8yUHzt+FLVr1cbiJcvRo3dvjB41EseUzAQafCt5mztnFvIXKKCMahZfcm0YYTY/sh506tJVDPL0mbOwYPESFFW62nx/1gRei1+5Zp//wAioHtDRpM1Yt34Txowdj/4DB2HegkW4e/s2Lpw/p1us/lBMLTh+pYLf/JcTk9ehMJcTs4/il3CbbPfZ+xvem32hVpiOA2ZOny76vUHDJvD64oVQoUOJbP2tSasfektubu7Sn+Dx0xe4e/+RLPcePMbtuw9Mld7d3XtPE+x3yQpLw0nnkM1/UaNElYiX/cA4yvuOckgZPXL0NfuNubi6SHMhm7F/FCHykVLRMN3Mpr4vXzzlfHQmU6dJiyJFi5p2DABeU/oMGTBp8hRYW1lLRpX9PBcumI+OnbtIM0zs2LFRrkJFlClbVs736JEp26rRBAadSmb7Zs+cgaoqKOnarTuqVquOEaPGSP+cdWvX+JIjKh0GM6wj6dKlR8FChRFDRcix1MJI24DyzSY8dhJnX00ex4VNPBw4YWml9lXfGXQFJQBiebwOBlipU6eRchjUxYkbF7Fix8Gb12/8U52aEIoSF8nURFF6nAMXatWpK33E6tVviGzZsuPcmTMiU5Q/v3qS/csuXbyIc2fPoHXbdmp7WNnXL8z2RFdynyJFSmVXiiJmLFM9YJcrAx7H8phVYoZIjLaCtuX5s2eqjkSQdf5dh3+wPDav5y9QEJmzZJU6wCV69OiInzAhXqt64N+1an53viJKtKhwV36Cq4uLyASX129ew0n5DUx48akyeDZkKGKkSMrRC4fPSn+LDCnH79MnO+mCZGVthajRooucuSl/h9u4z8uXz9U6F9HL9HHs7T95y5QpC//k6RORSXaxW7liOXLkyiUDz44cPSzJMWb/r1654nMNfxNBSMMpIxTWNC+T3yWgG2J05KaRY58YR2W4+DDVXcfOndvhoNaxX+WIYUNkOXLooAzooZPJMn90o6k0qGBev3qlzmFSIDzGztZW+pvRqeV2KiX/yuJDz54jJ3r37S9KcvGiBSiqHNJMmTJLR10ey3Q3z2OhBIN9ijSaoMBAx1UFTeGVIabRoixSjmyiRFZGy8XHULFuuLo4Y9jQQTJ4ZurkSWKA69etLVMDcTSjEc2yDAY7qVKmwqGDB6RpkM3gHKFopRzOtGnSyX72ShGyvv2o/rDchw8eoGb1Knjy5LG0LlA5Ojh8VnXoI2LGjOm9p0ZjGpAWI0YMaSbevHGj6E86bxzVyiY+9iUTXa8Mq72Zw8e/7MO4cuUKZFaOaPbsvrPwhPuwvIkTxsn0byOGDcXNGzelK1LN6lWxZ/cun3rAukMHNEvmLNJEzmMjKtl9/PgRvn7xQmalvyW4+2wvhluVLscFBDNGb9++RW1V365evSRdr1gP6Iy8f/tO6sGP6pLm90Pse7YcsLf7hOvXr4mupFzcuH4d6dKmU/IaS7pAvFfPnokx7p88eQpEixYNx48dkX6S9FfYfSNunLhIlCgxcimnkEmn+/fuisxRJ99U2zNmzCTl5cmTBydPHIejo4Ns5ww5H9SSU/kZ1KvWyjldNH8+Bg3oj/Fjx+CZCoTWrVuL9et8Jxv+FoLUvssK7d/iF96gx8pQnVBOI/sv0kHjiO0PSvkwK/jixXPs2LZVpp84f/Eqjp86K8v5S9fQqHETHDpwQCo6lVZA8IFSAKik6Ii+esWMjZUcw+kFenbvKgqDTd1UVoxsKVR+YeaSTsCxo0dk2pU27TrIOioT9qfgtABOjk4yVQWb7HlejSYw2C/HxiYKqlStjqlTJmLSxPGSle/Xt7f0Ry5Xvpz3niY5pvNZv34j6czdt/9ADBo8FH1UsNNPfU6bJq3Io7EvlSNHI3K6lBHDh2HRwgXo3aM7ypeviFSpU4uT2qljB3Tv0lkCIb8yT4NuXl4MJed0dDu2b4clixbKHLR9evVE3nz5kT5DRp99NRrqehpaZhz37duDvr17YeOG9RjYv69yJj+Lbqe8dO/aBR3am6YUovxxefzwIQ4e2Ieater6a0BZNvvpc8Q25Z51wagH/QcMEj1vyCL3pU2pqerB6dOnMECdf/mypejUoR1y5s6NHDlzSYJioDLeLZo1kUDL1znp6Hp4+ji3rK90VJkk6dalC+bOmS3jB7p26YQUKVNIXdD14M+DjiK75OXJm1fJSD/RlcOGDsY2pTubt2glssypDsuVLYW1a9eIv0C7X7lKFcyaMQNTJk+UvsPjxoxCw8ZNJYNNBzJDxozorXTksqVLRPaPHT2KZs1bilyWKVdeyZu9zO29ZvUqpVfbwsrKWga7FS9REucuXsGuvfuxd/9BbNqyFRmVjh04aDAGDx3+V8pYoI4lbxgron9OFbfxAXoq58zAQ+3L6HLRgnmoVLGcTCLKuSg5hD9lylQyv99T5alzOgf2bWEZcg5PD9Sr3wAPHj7A6VMnZcCQoBQBt7NPgofahxGocUynLt0QL348lC1VAo3q10XpEsVkygnOWWWhBGfpkkUYNmSwpJr96ydDhcNRh2NHj0b9evXFWaVSypI1m2RwqLT69euDBAkSIAkHXWjHUvNDKJteKkhpjw5K5jmJ88wZ0ySgmjt/ATJnNnXaNqDhTZI0qXTNYDaIo2U50pDfOaKRcm5A2axUuQrGjBsvE+syy16vQX0MHjZMZJlNjLFV5Hzz1g1wFK55poXlcMquxIkTy2fW26hRo2L23PnKGOfEqhXLMX/ubCRNlgzTZsxU8m/tb53XhFwot5yaatr0mbilZGz61Ml4/fq19INMljy5yBW7UnCULJuTDceS084VLlwUBQoW9CX7vlCymjBRIlM9UPJvXg/Yd95vPShYsBBmzJwtGf558+bI1HETJ08Rh4FyHy9ePMks+R2ExlYoXitnU1A1Vcn4F8lOsVtU2XLlsGHdWsydreRfBXGz5y1QwVcMqSuaPxNOh1W6TGksmD9X+svOnjsPpcqUke591K9hlc5ktzy2sFI2Oc9q9549sWnjBkla9erTF+06MOH0RXTslGkzkFPpS75c5a6Sr8VLlyNffo4id5GM55LlK6Wr0vRpUxA3XlwsVHWDXTooQ+b6lGWlSJVKfA5z2f6bCKV+WIC/7KOdPVauXIm0yvunw2VeyXgYBymwublwkaJysziy287OVnnjmbBt+1Y4OzpJJFmgQEE5hplMDoQpV76COHvGqakMqDC2bN4kjhz7vPBBcD2VFOfiS66MXvYcudQ1mBxZHs+HuG/vbhnZzcizWPESSJYsuSgqTubbrm1rzFHGM5e6Br9KjQqH18IRgIxUmGHl9bDfxYcP77Fp/XoZKV6jZk2laEypb40J3qcoNhGlP63dZwfvtRoDyq158x1ljfIToGH9CZixMYfRLs/hqcqeMWM63r59I3Ot8RqM+kU4QpJOr3l0zOsyD7p4DLdrY+ob3kVORxYtSiQ4OrnA2cVV7lVIhHJtyJYh15QZGt95Kjh5+PA+xk+YLNuMfShjlH1zefyn8DqMcxBeAzOQlHFmMc+ePS2D0fjCAnPdzX50fHTmddG8HhjXHFLrAX+/Rfhwot/tHZzgqpywP1XW+RwpJ4aM8C/npubAHnaj69GjGxo3aYKyZcuLPPB3GnrbwFxu/S3PTI4oQ/SDKG8/kiGWw/3+dBljt6zoUW28v30jUMfS0dkVnqqysj+C+Q00YITIm0OnkMXQ6LFJmv0WjOiRx3E7ke3qhrMT7HeofTlggY6jsT9hGSyLioujEs1hWVQcnLeK52em5ssXPixPmTrI0clRBh6ZC4M5jFToULLZ23w7y+U5CZsVA7lFIRLeD+1Y/j5QXhkk8XV7FStVho2NjS9jqvlnsPZrxzJgKH/sPsQMffkKlWRA2n8hf7wOvh54+7ZtKFW6jDRv6nrwc1C3/y2OZUDQ+eOAGvaDLF++gpaRf8AvOZYOSok6OP5Zrx3itTLLeerkSeljwQ7ZWnCCF4pM1MiR5F7b2WvH8neAz4KzLjAI1PIevBiOZfQoNirYdoaTCrj/NmP7T/ld5C+U+hdWOUa6HvwaPo6l0u/iWPoz5+PfgDFzgN9ZbTQ/Bx3LGNEie3/7RqCOpau7h2QB/zRYEZjJZIZTK5fghxJjZWmh7nNoOOsR85oQALNh1paWMt2Im9KL2q/U/K3Q4bLibCiurtJSqNEEBGfliWT9bWo8g0AdS/KDzZoQihHFavnQhBS0zGtCCpR1kXIt65of4F9GO/A+lk6ucHD6s5rCNf9/KDK6j6UmpEAFqftYakIC1O1/ex9LTfARUB/LIM1jqdFoNBqNRqPR/AjtWGo0Go1Go9FoggXtWGo0Go1Go9FoggXtWGo0Go1Go9FoggXtWGo0Go1Go9FoggXtWGo0Go1Go9FoggXtWGo0Go1Go9FoggXtWHrDN2toNBqNRqPRaH6dwCdId3aFm7uncrpC+bxtQmbkV589g+FdrHTmwoULB3d3d5/y/wv4O5ycnBAxYsQgTQbLd+JyLw8PD9MKf+BvY1lfvgT9lVjcP3z48FLu7/wqSj6rkDhBOp9p2LBhfd5IwVdaenr6/6zCqedIGaFsB04oVQfCStnBVQ/4SjZepxev0XsdZSqgso3fZUA5DEgGg/67/h5410LaBOn8fdTNhHLjV9YNGTOXqaDImGwNpDxDZlmMSb/6X96vwPJ5np+pF7wHxv6B1Yu/Bd6Lv3WCdB8ZU8+P8ufl9UX8mIAwnr9JPuj3eMn+hryYl8d9aeuN8nzqj/r71Z/tfwu/NEG6o4MDWjRrgvx5cqF4kUIoUjA/ypcphTWrV8HZ2Vlu1q9CB+r8+XOoUrE8Pn788I/K+ifw4R88sB9lShbHvbt3RVACgoLE6x41cjiGDBqAMGHDqLXfVzoK1adPn/D61asgO5Y875MnT1BO3d8H9+8Feh2+UOfi+zo1/1/4TJ1V8DFl8iRVB0qiUoVymDp5AhxUHfEru5SpGVOnoHXL5nB0/H67AeXJIoIFdu3cgZLFi+Dpk8dqXRCfewCEUXLz/NkzdOncAWVKFEMxVW/nzJkDzy+e8hv8wmvj7xo/drRcQ5FCBTBwQD8JtPz7XdOnTEKbVi3UdscAf5fmz4Zy4urqhhnTpyl9VBIVK5TFxAljYW9vL8+ccvvyxQt06tAOxYsWkmXxooVicP2TMa6jLRk/bizKlS6Bykrnz5wxzUfGuDx+9Bgd2rdFqeJFUa9uLVUntqsj/S/vV2C9ePzoETq0a4PSql4UL1pYrvmLOBn+1Av1G+3tP2HY0MEoW6o4ihQugKFDBv1ju6f5b+Aze/v2DTp36qB0YkFUqlhW/I+A7CwdT2dnJ4wdPUpkhcds3rTJexttbmi8eP5cdHzRwgVRvWplXL92TcrjdjqbGzesR4WypVCqhJLpOrVx7949kcOQQKA1hN71tWtXETt2bDRq3AT1GjRApixZ0KVTR0yfNsW7QpoqJT/T6bKwiKD+Wvhb+Uz7WHjvEx6flaK6ePGCZD9otMKFC++95zfCW1j4ehgsl2WYzm1CDLQqM5TZOelsme9nOs50fZJ18V5Pxy9tuvRo37ET4sSNq76bolHjPMbvoaDQ8ePfRw8fmoREncNCXZ+UyejEGysra2zftlUZ945wVxFfhAjfv6TdL7weVxcXXFDCToVrXJ/cF3W9hv9q+q3frstTRdBPn5quS/P/gwpjhjKGq1YuR4OGjaU+bFPPePKkCbLdeF58LmfPnsH48WNxXwUIrEPGNnMoX5Sjgf36iKN26eJFuLi6Khn+fl9zeJx/5RFu+/j+PZo3a6yCmtdo174jqlarjmWLF2DF0qWSafeNqZwJ6lpXr1qJWrXrommzZjhy+BBGjRgmMmX+u86cPqX2HacCn/tSTwK6Ds2fDfXwvLmzxPGqV78BmjRphr17dmOcCj4InatOHdvjwYP7aNW6LcqVr4BJE8dhw/q1vvSgAevOxIkTsHnjBjRWZdVv0BDr1q4W55L6jOW1b9da7EHnLl2RO3ce9O7VAydOHA9ygP2jevH29Ws0adQA9p/s0UHp+oqVKmHu7JlYt2b1d9fMctxUXezauROOHDqk6kQLuQenTp7AmFEjfPbR/Bnw+bso20o9y6RNh46dkSJ5CjSqXxdXrlz2V2aZNBo5fBjWrFmFRk2aonyFCujerTM2b94ouvDTJ1s0bdIQHz9+FJmNHiMGGtavIzqfdnnZ0iUYpAL0smXLo03b9rC2tkI35Q+8ffNGZP5vJ1DH0lR5vqJkqdJorW5O23YdMX7CJDRt3lx57xu9I9hQPpXs1s2bOHzoIM6cOSXbzJUCHy5TzxcvnsehgwfEqNJpFMdR3eh79+7i5s0bPmlmg4vK0Xr6+LGcg2XY2dkpI3xBRdSm5iiu+/Dxg6r0xyUq5joudrYfce7cGbi5u8l10HnlcTz3tStXxGjyWJ4vevToyJotGywtLSXdTUeWGZnTp06q33NAOQqnlTPdQbKUjo6O4qBGiBABbm5uyhE8K4b4wYMH8jt47lvqd9y6dROvXr7A8ePHcFUJr8nxC1wZ8Vg6jbwuwuu+e+cOzp89qxxIT6kAjKJPHD+OI0cO4aT6ze3atFJR1Uj5fTxeE/zweTDzeOLYMTRQRrFlq9biWLZQf8+f+xYIMJih3E2aOB75CxQQBaSk0bsU33DfPbt3inEeNnKUdMNQhZjaAP2B5VO+mDWhUab8+X3e/P5KGdBkSZNj0uSpqFm7Nnr27oNqNWrhwMH98PKTPQ+rlOezp09xYP9+9O7bXwwulWD7Dp2wb99eqWv87Tyvrapjk5RzkL9gQamzfk6t+Uvg83ZycsCxo4dRW8kP5aFBo8ZK97cX/eni4qz06lnJio8dP1E5ik3Rq3c/lCpVRgVa26TZ2ByWR1twWjllTZs1R/MWrdCkaTNZzp45I3rr8aOHePH8GfooGaxZu44y1N2QM1cunD19WupJYFDmufRXAdq2rVv8rRe8hpevXiJN2nSYOGUKatSsJecqX7ESDh7Y573XN7i/ra2tlDVpylQ0VL+/XfsOaK8ckmPHjoou8HsOze8LnyeD/SfKjxg3YTIaNGyEMeMnIGPGTFi6ePF3MkZ990jJJH2ZQYOHonWbtujTbwAaK52/YN48uHu4K7t+XPTjxMlTUFcFXxMnTUHcePGweuVKVcJXvFEOZJduPdC9Zy/UrlMXo8aMw6fP9rit/IKgBkt/MoE6lgZf+U85XFxYoWxsbMS5Yr8jfqfTxOZhNg8O6N8XLZo2Fu/95o0bsh8fLNPK/Xr3RrnSJdG7Z3e0aN5Usnp0lnij6Sy1aNoI79+/l+88ht59/Xp1RJExiua69+/foU3rFhI9yjWofVcuX4YK5cpghyqP65jh27FjO/r36S0O2YcP71WE3Q6tWjbH8GGD0aJZY/Tp1ROfP38W5UGHls0jL148F8eOzTwd27dTEctQyeQ0a9xQRbBuGD12nPx2/uYP6jp79eiGhg3qoZm67mqVK+KcEl5ez1pl+Hft3Innz1/IfVmuro99c+iEBwWqZl7XhfPnUaN6FRxQyo/lPnz4QKKu8eNGY8WypWjWpBFsItlg6LAR0qTq1ynXBA+8r5aWVogZO5ZkqtnNgc4k5Tte3HiwUBGq956YMHEcokaNirr1GoB9yAJ6ItzWtHlLbNi8DTmy5zQZ5ACeH7PqbK52UkENm1/evn0rn7nO/Jlzv/Tp02PB4iWIFTu2ZIIop/fv30WyZMml/pjDemsd0RqdVMRdoGAh+U0MlihLXzy/yHbKOs8xYcJYxFBReZ069SRLHuAP0/zR8FmzhSVWrDi4r4JlGk9nJ2dcv34dsWPHFT2cIH589BswEIkTJZZAm7JsofSVB/vd+pFhlmdtbS0Znbv37iqdaw8HB0fcUHUnfoIEEsRHjxFT/t69e0daeF6r4OiF0p0JVfm0OQFhXi8YIL17510vlNyb1wu2GmTJkhULFi1WdTOabH/37p0EdcmSpfjOSWS5bKWbt2ARMijng/WCtuLG9WtImDCRsjFa1/5JUO+xtSVlqtRInDixdF8Kr+Q4Tbq0uHLlkvr+2ZdupGN5/eoV8SNy5MglMkWdR1m4f/8+3ij5PKOCnkyZsiBOnLiS0KKMJ0+REhcunJfs6MBBys9o2Urkxk3Vi5s3r0t/xFixYnsnmf5ufuhY8obfvn1bOX7HJPs2Z9YscZo6du6KiJEiyUPYtGE91q5ZjXkLF2Hv/oM4cvwUUqRMhfbt20iqmM7aKuXJM428bsMmHD52AjNnzVYRxCNp/vXy+oqy5corg20vGUWWSQV24MB+9eDioFjx4qqye4qCSJMmLeLGjSvb+ICo2I4eOSJK6oRyNrmPl9qXGb2s2bIjWrRokmmxs7XDzt37sGffQWzcsh2XL1/Egvnz1LmUExsqtDhyIlxKySyYN0eEY/W69Zg9d4FE5k+ePhajS2ELEya0dBHIkjUbjp04jZOnziqhTYWVK5arw0Ojd59+KsJvh9RpUmPt+o3K8Rsu9yAoAkV1ZaHOcUfd81Ytm0lTVN9+A+WeTJ08SRzbNes2YM78hRg8ZBju3L2tjvmqhPb7dL4meKARYZ8rZjlYB8qUKoEihfLjwP596D9oEMJbqGBGBUjsK3nm1GmMHDVWlMiPnjdlwl3JlIcyzOok3mt9w4CCWeuOHdqpAKaxRN7r165Bo4b10VMFNubdJgivlVkgrmd/ory5skuA1r1Hr++uh9+jR48hTZOsZ5R9B1Wf2IxTolQpyeTz/Du2b1NB0zmMHD1GvnsFYuw1fzaUH8pT7779cFEZSfYPY/8yZgMHDRkqgTsNdK3adRDB0tI74H2I3bt2SrcLv8ELy+M+dERZP8qWLoHCBfOKHPftN0Dp3lDKWUuIrt26o1uXTqhcsZycL3mKFKhZq5YKyP0f7MAyb9y4jrZtW0uS4vLlS1ihAnjWi769e4qu9lsvGNzT0Ldv1wZ5c+eAi3Iwu3TtJjbDP1iPGPAxOcD9mQgZPnKU/G6Wp/lzoB9ipZw/OpTGs0uQIJGSo3Cig31jGiNBWbaytpL9qfHoFNL+MjCxtf2ISN7+D7dT1hKpQIh/KWeGTO3Zs1vGpTRWcsnudpkyZ5btfzs/dCzpsDBr17RxQzRv0gi9e/cQDz1qlChy41mB6eQVK14CJUqUEmPJB9CqVWvYqofJKI9O2sGD+1GhYiUUVftxHzZLtG7TTspgEx0jxAqVKikFtUMiRjc3Vxw6dBCZM2dV2+LIOsL98xcohJtKqdCpfPniuTSLd1KOLlPdzHi+ePES9+/dF4f0w4cP0pScMWNG3LlzG8eOHsGjhw8QP34C5ZAekkEN5q2VX5RAvFXRLJvGY6hIms2FWbNmlQwOy6IidHf3QMFChdGseQtxXOPEi4eUqVNLRtHdw02cVFOGNQysrKzU743gXfqPoaDeUZE7O8ZXqFAJ3br3VILrJfeZ58+eIyeiRImqKkg4ZM+eXRwIZhXMlagmeOG9pfKhcWXmj45Yy1Zt1Odk0qGbSuTly5eYO2cWevXpi6RJk8gxXIyMvX8ExTixbAYt4ydOwqw5c5UsZkPlqjUwb8FCjBg1WuTLvBwaXNYvOrplypSVfpZUZFs2bfRXRuhcsn5yG/uVsV8Qg73e6nfw2p89e4p5c2crp7qfRPvG72L5Af0uzZ8Ln62H0m+U9USJEilZbySZFwb07CPp6uIqupgyQxl4/vw5enTrgoIFCylHsPZ3ThrL4zHbtmxBWqXz69VviNat20rWc8vmTVIW687BgwckuVCnbj3ZzoGPbMViEO8fPE+6dOkxecpUzJg1G+kzZJAmR9aLISqQp+z6rRdcx6Vc2XLKIW0vmdOtWzb7K8fUw+waxRqTP39B6RKQIEECcV6pC/i7NH8O4vzxg9ljC/AZqtWG7Pjswa/qi3GIxNZ+Djcvjj4Ay0+u7AWb3itXqap08CYZQEZZ/Nv5oWVg1NZHGZkz5y/h9LmLuH33ATp06oyuKrpkJsOkGF4gTeo0ykiZms+YXWTTCG8ulQbX2asIIJVyvuhE8runctSYBRLHUj1E3mwqlrt370qGlMfdUw5Ww8ZNZH8DPvDiJUrg6dOnyoF8gRMnTiiDl0gplTrKwXQRR5YOpKVlBOTOk1ecT0cnR4loN65fJ8psg/prEzkyypQtr67Hd/aFyjJ3rjzYv28fDh86JANj5syZLX3gkiZJ6uPgUvGYfqv6Pd4LDfNXL3YbMC2E+wTWnOMLEVxmTOfJPe3UuYs0S1GJ0lnIlSu3KOhTJ0+KE8vrYio+Xrz4PtelCX4Y1bL/8Lq1azBg4CAxMi1bt0HP3v0wc/pUXFcyxxG0fIBsBj986DBu3b4pTS7nz52V5mjKOWXmVwwSn308FQglSJgIefPlR8ZMGeV73LjxpEwDBjK3bt3Cvr17JbNepWo1dOvRUwZMzFWywijbv+ugzLOJkoPybt24gTnzF4lc0cGYPHGC7M/6wt91W5X/+bMDzp07Zwq0tHP5V0E9fO/+XWl9YctL+w4dxbHs23+g0jezpOnQCF6oq5s2aqDkMiHGT5rioxOJIWOUrStXL2Pr1s0YMnQ4Wql607ptO+l/xoFv7GtPh9Xuoy3Gjpsg/Rl79e2PfPkLYMTwIcqBdQ6wzhj1Ir6qFwUKFES69BnkexzWCzO5pIxyxC4TIBGUXahWoyZ69O6DOvXqYfbsmT7ZKeOa+Zm2ZYtyOtmfrlTp0pJt6qXux5pVK2WABvfV/DlEixYdTs5O4s8Y8sSubx6e7qbBsQrj+dN2M3lDWXZyNskfD3n/7p3oSQYc0aJHkwQbE1HGMc+ePZPWQ04vtGXzZgm6MmTMKH2Lx46fhLfv3iqZ2qQdS8Ibxc76TAEz9RstenTxwNm/hg4aKyGVB2+auZHhjeaDiRotmnxnpMi+YcZD5R/uz/24hlmVvHnzSl+cncph5aAdZj5TK2fU3GniZzaTJE+eHHv37JIBNpkyZxFByJAhoyiPY0eOILNaxz5hdG4jRbJBdaVMFi1ZhjnzFkjfmTFjx6Gsilzl5EZgq66FHxn9Mgs6csQw6Wv55MljjBg1BjFjxza7FrWv2t8X3r+NcJs4lGb7UHCZjqdg+TnSBFeq/em4UznSeacgc3/eK47IZ0p/8KAB0szJbSNGjla/PYqPQtcEP3yszNBQiVCW+FwZkNio+mBlHRHv33+QQTvse9OzW1fJ4CxbskQGOIwaMRw3b96SZ8/M8s8GAHz2HAjGfsu1a1TDyRPHsWr5ctSoWlmmTjEfSMD5MK9dvSIjup1VQGVSeEDkyFHkRzg7u6i9vpquQwV2pmPCSX+z9m3byjZ23UieLJkcS6PKQQyvXr3y+V3Lly1Vv+up1I3bt2+FCCUZkuBzZ4aR+pjBBPUYZwCg7mc/MgYVNKzsS0b5K1mqFGbMmAMrtY79JE0y903G+J1Nh1JfVHlMIlBX0Z5QNzso+WUAxkQEs+8MotkqFFPpbiYfOO0Ry/AL5Y7dkejY1q9dE+fOnsXiBQukXnRVutHVLKtIGefsI2NGjoCbC5s91XpVL2gzqHJd1O81v2aWzcB+2JBBePXyldRdOgtMLoRX1+no6GQqQ/NHQHnLkycPHt5/IOMn2IWPcsYuRhkzZlb6MbJ85/PnvkwS0SFkYM1R49Z87kqGqIeTJkkmLZQs78b163j/4b3IBe3DYxUkZc2STWRk2pRJ2L93j3di6It0b6MeZlejkGCrwwxReH/+DjYVLF68CNmy55BRroQ3mJWUES2bmkuWLCXRHUeJM+MYI2YsUTBsMmCH2W4qMo0ZK5Z0eqXDWKNGLUSOGhWuyshxuombN2/KSEEqrQiWVpL127x5k6yvWbMW8uTN56tPAhUA92WFZ58XRrTNm7eUPpbMiq5bu1aMIZsrU6RIKQ4t+1OyH2aZsmVhaWUtzcoc5c35KzlC8PnzZ+Ikc6Qvld+Afn1QqlRpTJ81B1WqVEXt2nWlWUiUXugwcl46GcwI8Xro9LG/HZtv6HRTMd2+c0uVfwDVqteQ30/F9PTJE+lWEDFSRMSMGVOONaDyYkS0fPlSyRLUqFkb8+fNxZXLl1C+QkXJxvbp1UNdYzOMmzhJXVc1dX9qS984Cm6Qs6LBRAQL05RNnED3b4fPicqHHbbZT8zI1syaOV09t9AyfQWfM0e6Uu6aNGuB+PHji8yvWrNOBT6ZJABq1KC+ChjiSABkOJh87nTc6LA1atQYsWLH8aV4eG5LpahSpEyJXLlzS2YmX/78MiULO5bHVMGXEdBxX/Y/3rhxPU6dPinXyQFlUyZPQI6cuVC3bj1cv34V9erUQkRl2HPkyKmcRNNcbKwDzZq3wkdVd+gwcpYDZl/ZvNikaXPT72reQspnn7rVa9eroC+N1ImQAO+xZQQL5Wx7wkP9Zv+cnb8ByhCdPjqObA5n/2FOLzV75jTRM+yTyAw9u0YlSpQQlSpXw4OH96U+vHr5UrLoHKhQv24d6aPLkbc2NpFE/9LQUiaZ9Z4+dYqch7ONMPuzeOFC07Rp6vxHjxzGrFkzZIqXUqXLqrryvYxJvVDOLBMPrAu0T0a9yJ49pyQV/NYL6l7arvDhw+HkyROYNnkSChYqJDbg4oVzaFCvrnR/ypAhg3RxOnvmtMxFSHvDlgBTH/dIMkqYOp7l/o1wUC71u5tyrDyVnvobZD12nNjYs2eXJJ0YwDDwP7B/L4aPGI3ESRLL55YtmiN58hSSuGICjSO4Vyk/h8//0MGDmKX8lR49eyGb99gN+jwcYEuZnjt7Ni5duoBhI0ZKNzsXZa+nTZks+p2DypYvXeLjD8VTjunf4lyyZcDK0hi8+o1AM5asOJwuZdrUyahWpRJq16yGQvnzorEykAkSJhAniqllTjnB/mZ1atVA+zatULVSBSxdslg9tFFI6O2QNWzURDz28uXKoGWzJmjYoK5kdHhhbEKn8NJZ47QVzMoxS1hAVXr/DBeVT5FixfFQGT+O0EumhIHOZ648ecFpgpjJy5wlixxL5cLpKzjakJOYdmrfDlXU9VE5snmDjiKNPFPenCyXkQUd5DmzZ6J08aLyu4sVKYQmSpGyOYXl0TFlJG0KWk2VzrTOVT6zPCo4np8dy2dNny73kn1G+/ft7ZPpVT9a9jfgoAhG9yyHAj577nwZEU+HkoOCypargDGjhstk7rwuTszapnVLmarJUKKa4IdKgEaQ/RxTp0kjc7iOHzdKlAufkZExphKhweEcaFzHOkGlQyJGjCSjC2/duOnrWVEuGNVmSJ9BWgbUCu8tJridEXamLFmRVQV4mbNmk4WfGVUzS2nAa4ihApbZc+aLMzpm9Ehxftn/maMUWZaVVUSpC9evXVXHhpdmPc60wN9Hmad8TRw/FpMnjZfuKPxNxu+iwTF+FwM2zd8HZYgZGDZLc6DBzOnTMG7sKCU31tJ/MZYKkk+fOiUzIXAgzNgxI2VyfS4LF8xTgT7fYGYj/XSpY6nXORKb0/YkTJwYU6dMUnVnjAzYmTl7jsgpnc9pM2dJ9yZm25cuWSQ2hfMDfuHANn+gLFNmWS+yKENvXi/Y4kR5NeBv4hzFbKni59FKxufPmyMBO/sOM5tqbR1JRpjfuGHS8cymsvmSAzSnTJ4odYLB4tTpM8XRYDmaPwM+K8rvnHkLJckzYvhQCZ4XLV2O7Dmyq2DRQ8lSFNjZ2eLundsiO8xacrBa2fLllP8zRbrQjR4zDtVVEMLxH3Q8Fy5ZqnRjaAwbOgRv3rzGkmUrZOwIfQHOdcyuJJz3mHOfcqDZ5KnTkS17dl+Jsr+VQF/p+NH2E5YsXYrXr19JRSZ8SOmVESxTppz0V6HzRMPD5oydO7bh0aNHUvGKlygpzdF0PAknZ2bGbvu2LbIvHS9OTM65/DiakE2MbLLg/syoRIkaVRSBTG3yHaHUeT0kK8rKznk2qcB4jYwwGcly0l5jHQWFzX0895vXb0QoypQtJwaSv4cGdPOmDZKV4bQyHJ3IMkqVKSuONbOFLJeDg3bs2oOTp06q63RDxYqVpXyeh/NdcpoMdj6nE0jldFpFKMyKpkyRCtVq1JD53Boph5qTpnbp1t3n3hDuzz5rnJCVmVoOWGLfPmZbDx04gJKlS2PShHGSEShUpKjSrJyo2BErly+Hs1LiGzZtEScmkMcZbPAcIfGVjoaTZZpE/6v35y+y+IUywe1GcMOMYI9uXVUw0xFFixb3pVy4L2WU+wbH82NZPCevi2XzM8smMkK8Wxd52QHl11R/aYS/79rBuuF3nfnvCinwDoS0VzoGJuuUJ34PyLliMzJljH0zmSigrLMVi0mEgOoOdT/1upFk4Dl4XHDqs8DqBbOtvGb2nWYrnFyzzz341rpgfs1/I7zff+8rHflKT9Pz57MnfM78zKx8n9490X/AQBkgS7lg0kmcTCWT6ibIfaA/Ysikr/KUbKgNPnqd+1KmuS/rifn5/iYCeqXjD98V7umllID3TTHgTadTZH4obyQdG1Y+rud2v8aH27gP9+UN5naOmKbjxpvPpuCjRw9jQP9+WLhoqTS1mztffqHzx+MYIRgw0uT5zdcRPliem395DMs1FATXMWtEZ5EdejmnZdfuPWW6izBhOCm5HebNmY1TKlLfuHmLckxjyCAdRi4GzOBQEPlbDChYXM/z8PdySg4OABk6fAQSJUqi1vu+P3xzkKW6DuN+EAo2HfXLly/L69A4l2bp0mVFkNnkT2fzmXJaVq9ZL/sG8jiDDZ4jJDqWvwrlnk2B7A/JgMd4tv82vI4zZ05L0zu7eJB/Q17+dHiHQppj+atQxk6eOIEPH9+jUqUq/5ms/wy8Zo5At7X7KMHWn3DN/y+oD/5WxzIg+Pv279srwQ+DCr9+iyZgfs2xdHKFg5958v4f0LFj51f2e2T/xXYdOkoa+d9ylMzhb929cwemTZsqjiabceyUA8c+bnwjCZvYf1rxqDLZx/LIkcPSV5NTd/xM5MJronPKdDybK9Ua6UzPt/Bwyo0Onbogbdq0Po7y/xs+E+1Y/hyUcQYD/mfg/z14HVSgMpm1Jkhox/Ln+F1k/Wf4E6/5/0FIdCwJnz1lIKQ//5/llxxLD+Wo/FveOy/jk90ncdrY6TtUmNDijP0XcO5O9h9i0zWvh33fokeNKm8kYX+MX4UDnzgZvMyd+ZOwcocNE1auiQvvF7Oz7OfHzKhMsv0vEl4JFB1c93/5vBrNfwFHKrP+cjADF43mb4UJA8o6bQrHHWg0AUFn3ELJil8CdSzpVP2bgsWLpAPF8wZyWf8K0vxvFqmx6ft3eOOIr+tSt0imvvkP7pVxHf9WllSj+S+hXmKTKXUTF43mb0WSGEq/0/b/F7ZF8+dgSnh9P6frb9EUrvmzoMjopnBNSIEKUjeFa0IC1O0hsSlc82sE1BTue1SORqPRaDQajUbzi2jHUqPRaDQajUYTLGjHUqPRaDQajUYTLGjHUqPRaDQajUYTLGjHUqPRaDQajUYTLGjHUqPRaDQajUYTLIRIx1JPn6DRaDQajUYT/ATuWCr/i+/jtrKy9ln4nRMFm8Pv3BY27PczsBM6clZWVvKubgO+rpHv5w6qk8dz8Nz/1Cnk8ZyrK5DpO38Iy+BvMd0TK/ktGo1Go9FoNCGdQCdIt7Wzx5YtW/DhwweZgZ+7Ro5sgwIFCyN+/Pjyvms6fE+fPsWJY0eRK3cepE6Txtd7sOmEubu7Y8vmjYgXLz4KFios627euIGHDx6gWIkS4pwF5ujxHA8fPsSVSxdRvkIlhLcIH2TH0HAkCV99eO3aVRzcvx+t2rQV5zCo5Rjw7UB828xx9Xt5TRbqWvIXKIiUKVPLu8VDArxneoJ0EwwqTO+0p6xBZMOQf8oeZY4yw3tGSfvi6RmktxXxWMqneXmE5bE+GHLr4eEJL6/gf/sRzxE+fHg597/1WtffFd7pkDxBOn9rWMqdyLFpnSdf92fIsdrOVwBSzgll093dQ/0N/A1FhozxNbmsF/8ElsP3Pbu5uvrUjcBgnWVdcnNz8/UmJV6TkSjg7+Y21oGglPk3wN/5t06QTvnkMzd+D/VaYLqN+1GujP0p79zfkAXKCsszMC+Px1COTLpaqojIUVB0/5/EL02Q7uzsjFGjRmL4sCHYvHED1q5ehZHDh6N6lUrYt3ePt1ENhxvXr6Frl07o3asH7D998lEwhDd+9aqV6NShPZYsWexTcQ8dPIAxY0bKe6+pEAKDD/fChfPo26cXXFxd1JofCzqvIXx4Cx+lwQfNz8vUNVxX18v3bP+ssmCZDg6f0bN7V3Ro1wbLly7BuDGj0aBuHRw+dMBHIWlCBpTl6ypQadywPsqUKoZqVSvh1KmTvpTNtq1bUaNqZVSuWA5DBw/Emzdv5LjAoKy6KgPZqUM7zJo5w0eu+Pf48aOoU6sGypYqge7duuD9+7c/LO9nCKWCBdaNZ8+eolb1qtixbavUP03IhfJIOahcsbzIeauWzfDy5ctv+k7p0U2bNqCKbC+BMaNHwsXF2ZcdMIfrKWOPHz9CdVU39u/d/csyxmtgALZu3VqpZ37tj19YV9hSduH8eZQvUwo3blzzqa9hVFkvX7xAD1WvypcthTKlS4jtop0wnAvNnwllwtbWFn2Uj1KyeBHUqF4FV69eCdBm83kz6Jg6ZZLStcWVXBfHrl07ZT0Xlkdd3qljO5QoVgT16tTG3bt3fOn+Pbt3+dSZZk0bi04N6Hx/G4E6lryBjDp79OqDfQcP48Dhozh55hxixY6NKZMnwUle92iqrBEjRsRpZVTXrlktFZ2ECxdespLz582BtbW1r3dKmiLgMAjNAn7g4LFi81hLKys5n1ojSoAP0ajwoVVZErWqB86H9+mTHcaOHoF5c+fIOu73/v17HDlyGBUqVlL7hJP9WAYX0+fwUgZ/D/9yHf9y4fHcb8f27aLEFi5eJvfi7IXLSJgoEUYrB9zePnClpvl7oGw8fPgAzZo0VoFRaDRo2BixY8VG547tJdBiFn7vnt3o16cn8uTLh7r16sv63j27w9XFNVA5odFdvXIFli9biudKGRmyd+bMabRv2waJlLw1atIUL58/R9PGDZXCtAuSc8lyeN0Bwe2Ojg5YqoKvmsqp3LdvL968faNlOgRDudutDGTPHt2QMVNm1KlTD2+VQe3cqT0+2dlJ96SNG9ZjQN8+yJU3L+o3aKgcxb3o1qWTZGcoU+bw++fP9li0cAFqVKuCgwf24+3btz+UMW73K7tcd/fOHfTt3UvVi1Y4d/aMtI4FBPfntU+aOB716taSIND+kz1CqfXc9v7dWzRuVB/Pnj5Dw0ZNUKBAIUxW+25Qv4/3QfNnQpljoN62dQtcuHBBnm30aDGUM1hLkkz+6USuY4C0YN48VKxUBXnz5pdk0vZtW8S/oQxT9z56+AhNmjYT/cvyaBMiqDpBuWayLX2GDKhTtz5sP36U5NpH9fdHibS/gSBZDDp2fCG9p1IUUaNGRenSZVTE+gIeHqY0ORVI9Ogx0LJ1GyxdulgZ0OtSEbl9wvhxyJIlK4oUKy6p4OAgnHIKnz97hiqVyiunda48VDp1w4YMRu2a1VFXPeCG9evhqVIQ6TOkl2MoKGeVYY4ePToKFCyo1nwVQZk2dTKWL18qkXaeXNklQ+To4IBZM6ajcMH8yJs7hxh4wt/5SUXEjRo1Ru48eUSJRY4cGSVLlcarVy/h7OwiSkrz90NDtGP7NkSJEgWTp0xHs+YtMHb8RKkfBw4ckHpB5ZIzV270GzBIlFm//oPw5MljvFB1JyBHkEHMxYsXsH7DOuRRhppZdmYRXVxcMEfJJmVtwqQpaNi4CSZOmaquI4xSbvd/qKxYH88qw9tJOb5srvFr8AnryCV1bmZp2rRtj8RJknhv0YREKCOUuzVKHsqULYfRY8eJjuffB/fu49btW7Cz/YiF8+ehQ6fOGDR4GJq3aIkx48eLfXinHDXWE3MoY+fOnsO6tWvQqVMXxE+QQK39XhbNYZ3YsH4dhg4ZJAkFY3/apTWrV+H582eqbg1EeCY0AimKdW6/CpZYL/v1G4BIkSKZ6oEqh9dJe5EgYUJMmzETDZSOHzpsuCQh9qkAUfPnwud+4fw53FFByKQp09CyVRtMmTYNadKkkRZMv44l96eeZmJg0JCh6NK9B4aNGIX69Rtg3ty5oj9PHj+ON29eY+r0mUrmW2H6zFmIESOGqiur8MXziyTYiimfZ8zYCWjRsjXGjJugApanuHrlsjQf/+0E2QtiZpFZQzaBMJNRuEhRVTFtpHKTL15fUK9efSRMmAjTp00RQ3bk8CGcPnUCbdt3gIVSDsEBs4rs88nmx9ix40qEzHOzmfHK5Uvor4x49+491X5hESt2LBQpUkyOc3N3w9Ytm5E1W3bEjRtPDPYz5ZzOVA4kHWFGHaXLlMGUyRPRoH5d3Lh5XRnXdihWvAR6dO+KY0ePihJqp37L2AmT5HijiYRKNH68+Ka+omq95u+HQUamzFnQrUcvyTAye0/jFMEigjQDUjnFjhMHb96+xUclr9z/3r270gxnYxPJp4uGOTyeWaBhgwehWtXqyJkztyixMGFC4+3bN7h58ybKl6+gjv2Kz/b2Sv7jYP/Bw8ieIyc8AsnUsAwGdXa2trh/75408bi7uX93DdyP/aS37dgl9YF12KjfmpBLhUqV0LBhY7gqJ5OOpqX3oEvK9N27d2H3yQ6lSpeBq6sL7JT8Zs+eU8nlUcSJE1f2MYcyli9/fmzfuRv1GzYSox6QjHE95ZYLmx0fP3oET35XupzbuHTv2QvrN26WbKr06QxEXFlO1eo1sHP3XpQuW1bWmXo+m64rW7ZsWL5iNaIrB4F9Nfm7Hj99Ii1S4oBq/kioV0+ePIHUqdMgWbJk0p3NQunpdOkzSBe7z58/+wqAqLvFAVS+Ru48eeHk6KjkwwOZs2RVzultvH71CidPnUTWLNnE7rM8BikpUqaS4N3ZyRHllJ5u2qyF0rWuUi8slY0IHdrUvP6jQOpv4IeOZXh1cydNGIeSxYqgeJFCyJU9Cz68/4AOHTv5MjxflbFjNMnI8fixY1i8aCGmTZks3joNcGBNFEGFD5yZyS5dOiBuvLgYN34CokSJivfv3uPWrZtor66JmURmJPlQTylhYoaRES8j7CuXL4thNpQdr71AgYIYOWqM2r85+qooNnHixIgTNy6mz5iDZs1boneffkogU+PSpYsifDzWMOIUTjatb9qwHs1btpTslX8Og+bvg3JQokRJVKhYUb6zeeTo0SPSj6ZUKRpZV7RQkSxVSKkSxVC5UnkMHNAPffr2k8DGr8Gl4eIydepkRI8ZC63atvUeDGZaT4Pu7uGOR48eonnTxihWuCCKFi6AdWtXS1n+GT6uozFlq0Hd2jUxedIEPHhwHy2bN0X9erVx+NBBqcMGrA/8HfxLBWjUbU3IhM+fjl/9+g2RLXt20W1hwoTFqlUrJWjPrJw5W+VIcr8zp0+jdo1qKFwgHyqWLyNJBf9kkvsyEGNZgckYdT2d1H59e4vsrlm9UpyAhirob9yogTSBszsTm+LdlD6mwxmYU2nA/elE0h753Z3X4qG20dHo3KkD8ufNDcfPDujatbsco/lz+fjhI6ysrXz5LEyCUYbcxdkzJ5TyG+xlsJoxsJhWnV0AbWwiw8nZGbYfbRExUkTl85gGUlLW6TsQDnRm16ccOXN615kwWLduDaJEjaaCl+zipP7t/NCxZDawUOEiqNegoTS/9R84GImSJELP7t3w5PHjb01wSofQiGXPkUNuahdVMbmNUalU+n8InToOJurYvh3s7T5h3ryFsIkcWZ3TXaIBi/AR8OD+fZPjp9YxkraxsRFB4kNnJBFOOZhZsmb1MepeKsJNpISBxpQZJ14/+32yuZwZTycVeVA1xogRUx3jW7FQQR07eliMdM3adVC7Tj05XhNyoHGicaT8nD9/TrpitGrdFjlz5RIZO3HiuMhexUqVULFCJRTIXxAHDxyQTuTmETJhdHxMBWRsYhkyfASsLK3lWGYrxflTutBFyf+mjRtRsFAhTJg8BZWrVEP3rl0k6DF3EA2o8OgYtGnTFjNnz5Ugj8pv/MTJmD5zNvLmy68NpuaHMEiinDBAp4PHYGbwkGESgHM0N5u8d+/eqXRgXUyeNh1p06VDm1Yt8Pr1KzGqvwLrTxSl3/v07S+yW6lSFWRSjuy0GbMwRZ0jWfLk8FQ62XASggr3D+gI1hW2rPF35ld1o17d+nB0dMT+/ft0F6c/GIrIFy9PmcXEPNgRHfx97COIvVfbDD0dShXC45l1ZIHczm5Ivsv7JuvmdYbdOJYtXYIBAwchXvz4Itt/Oz92LNVNYNNF23btldFsg46dOmPa9JliHKdMmSRevQ/qAfJmtmjVSvqoMAMYLVr0IN9IPkS/BteACsFCOZBZsmTB4yePcePGDXmojAjYdFG9Vk3pbNuuTSu0aNYU+/buVtfaRQYV8SHv2bNL+kgw4jCUEUXCS12b6Tu/mZQOm7ONzKN8V9t5LtlL/WVfnh3btqFjh3Zo0rS5ZGm1UxkyYUftA8rwtGnZQgxruw4dRd6lfkyaiJo1a2HQ4KFo3badcugmYfeundi1c7sp4PGWd8qUnZ0txowaIRl3e/X53JnTePvmrQw2uHrliuwXLVo06ffVslVrFCxYWOpi2nTpJTMfECybDgCbgDJkyKDqcgEkTZYUyZVhZv9goy5oNAFB2aODOGP6NEycMB7jxk+UrlDUqxyUmSBBQoyfMFkSCkXU+q7desI6ojUuXrggx1HOKYc/C1vAEiRIILKbJWs25MqdG0mSJlHfk0tgr4TXe8+ACeq5+Rtv374trW3MqNJ+DRw8BDVq1JR++A6f7X/pN2j+e/jYOFiHiSnaaeM5vnjxXFofjaDc0MX0AtgSSh/AWQYoq/3V8v79O+mCRPmIFj26DHSkv2Mc8/z5UzmGAQrXUfbnzJ6FsaNHYdTosdI/3tQU/vfzQ8dSUPWXN8zkbIVSldpK3VwLUyaSN90M7kNncuas2d4DXIJyI01lcKQVm7qNB28ODSAvtku3HqhZqzaaNG4gc1IyVc1RhewDySi6mlIEtWrXwcrVa1G8REk5jtMKPH3yBAULF/Yp61fgdVEIly5ehIED+qJ3334YPmKkKDlGJhRMTciBmUp2g2CmsluPnujdp69k6alYKPefHT5LP0sqGCqgSDY2opA+frSV49mPi8aZx3z8+EH6V+7ftw+tWzRH+3ZtcOTIIRw7dhQD+/eVcyVPkRL79+8XexrKu78O6wyVoH9QXqlIJ4wfK4PaJitH99HDh2jepLE0L3LKL/8ynRqNgWFsx40dg40b1mHe/IWoXKWq0vMmHZpCyST7DXNeX2NftvSw6wa7BlFWmWmn/P8MrDPsE8wR37VqVMPaNavEUa1fpzYa1KuDu3duSz37EXQMTHYrcFgPOKvJsKGDpc4YyQTW3y9fvODk6O1gaP44+Pxz5sopuo/9I5lsYvB//95dpFOBuU2UyPKdfSn53Jls4mhuysGNG9dhZR1R7DtlLkHCRIgbPz5y5cqFWzdvyGhva1UedTlHiGfMmBGRIkUUv4j6lhl+Ztxr1KwldYZyHRII1BOi6mBlOn36FDasW4tNG9dj4cJ5aNu6pXRirVO3nkSNvGHsY2k4bHyQHCFtrkzkgZlVcH7mOv5jcx/ns6xQroxSItUlsvBdiU2TnEu/GPW3/4DB0rzYUCmYO7dvycNiB1qOUnzx/LmKRF5gz+7d0u+Hymfb1i3Sry1N6rS+Mouenl9ktLsPvHxVvmkdz68WXqP3wgFMs2fNVMqupwxyiGwTBatWLJd7wyk3Ximh1c5lyIBytXbNGnTt3AkFChVG0mTJZMTpoQP7peM3g6sSJUth1KgRWKFk5NChAxg1cjhsbT+iaNGiIv+DBvZHh3ZtZe69JEmS4tDR49h34LAMLti97wCqVK2m5LwylixficRqOwfUcC7ZicpRpFM4dswoFUF/Rr4CBUU+/cJ1vM5SpcuiRctWMhqyY6euMnKXo3v5MoPADD63mddZTciCOpg6d6gKnBYumCfdmtifkfPzHVHyzKlVOIq6Tt26GDNqpEwhxPmNmaHhCFlmGT9+fC/TsEybOsVfo0oZ828idcqdlTLY1WrUENnlQMoOHTuL7DZX39nfzWgJo6Zmvzb2j6Q9IZR7Xh/nEeQIdHY1MRDLonZjYoR2i2toFzh4k/0r+yj9fvjQIaxatQITJ4yTFjtm/XVd+DPhc8uXN790cRuggvTdu3Zh9MgRMjtBo8bNEDaMaX7gShXKSVck2vBUqVIr5zE3hg8dig3r12LenNlYMH++jN2wCG8hLUbsb8zy9u3Zg6GDB4njWr9BI7i6umHU8OHKV5iBOvXqQ3k6Umc41zUHoIWEACXMEIX35+9wdHLG4cOHJTN4+tQpnFA3/dDBg4ijorjRY8ZLHy0ar+fKmePgmXIVKohBNTdyvIn8fvbMGVgrz79k6TJSsTmZKPvgcPCDEUEwYnz86DFq1akr64xyqJCePHmCe/fvStMEM4T58hWQJnE2Q3LkNucIZHaHTimH9fN66fSxLwSnJipfoSIym/Wv5HUdPXIYSZMmRZ68+UT4OJ3S8ePHkDhxEuQvUEAUHtexLDoOmbNkwdw5sySzxPmo2EGd+/O+sAmFI8iSJEkSIhRQBAvT3J58M0NIhLI5dcpEfLK1kzlT6VRyIBfl0dHRSZoEOV0Qm7hXrVwuU5yw6WT4iNHIlj2HyMhhJT+UoRq1akt2hwqNmRP2BWaEfP3aNUSwtJJpK9jhO3mKFDLSlo7q7l07lFPpgDFjx0uUbMi1X/iMYsWKJSNb6QSwaZF/2XGdryQ1r6sGPIbXx/6g7DOdMWOmAMsPKfDZWEawgLuHpzgwvEd/O9S7nIFjsnKuONsBMzyUc+pN9juMEzsuMmbKhHQZMsiMIYsXLxLHMnLkKCKXfDubm9IPnHrl/bt30tJkyBvvH2WKMka9ycyRXxnj+ZkQENlNYC67CVX9+PbWNPZte/XyJa5dvSKtVWzFYvkODg5YtnSx9Jssr2yTEURxG/vUHz58UNmsiuo6E6hze0odZHM76zCTKBxJXKxYCRl5zuZP/+rK3wifJfW7m7uH2L8/Xdb53NhliX3TT544LtNnMRs+YvQY5SCagnImhZYvXSp9dxlIUFbyKr/g5cvnWLZkiWQuu3TtLsk06kZ2ASlQsJCqD3uwfu1amXVm9LjxyJkzl8yXPXHCWBn4zODGqDO0AWySz5ot21/jI8gAJ8tvr+o2CPSVjo7OrnBSC+XKfDdWeCpaY6Q3BY9LYDfL7z7m343P06dNFWeT/RH8lmW+P+H5uXDdRqUE+vftgzPnLorTy2tlM2HTRg2kYqxYtUaUll/FxeO5r/lv45yBDGd9rVP7qRWyjscQ8+0G/q37G+Hv1K90NMkk8U/uuY2ywqiWTiH3YRaF60xZmq9YsXyZRMrTZ8wWw+WfzJNvcmXqikEjSFmW8lRdDGyqoX+Cf/UjJMJfT2Mbkl/pSAKST/6lXDLrx32ke4Vax4E9bBIfOmgA4iVMgG7devpqMSLBJWO8Bi7GNbJcBv89unWWrH+t2nV97JUB9/H7m1inCK+T2/kiD9Y1No+GBPgc/tZXOpo/W36mH8PP/H18CxTfqNe7b3/kzp1HdDS3c6HcmMu4IascUU7tYJRHeeFnYtyzgOrM30JAr3QM3LF0coWD0Xn1/wgfHueSXLJ4ofRV4zvF/TqBAcEHyuxn75495Bj266TDc/vOLTx/+gwDBw9FiZIlfR645p9DkdGO5a9DBfTJ7hPWr1sjWX5mTPwqIM3vQ0h3LH8V6nVOC8TgqW69BpJJ/LfknOc+f+4s7t27J1lMfg/E1Gm84T36Wx3LgODvY1M1m1LLlfs2HaHmx/zWjqUBnURezs8+WB7H6JR9J96+fa3WhEK8uHFRtFhxxI0XTzuVwQyfkXYs/zm/Ku+afxftWP46vE+Uc/Zn968v5f8T07nDSYtBIGZOYwbvU0hzLAmDfQYf2lf4OX7JseRoOF+DW35jOL8Ulb85vHb+Bk3wwwFXodQ/djXQaP52aFupX754+R6EqNH8bYhDrvQ7bScHRWk0AUFZCRf2+0F5gTqWHh6e0lldo/GLhUU4cSxD6uAdTciCCtQyQnjRiR6eOpjS/L1wQAb1Owfv6MSMJjCY6aVe9MsPm8I//4tN4Zo/A4pMVO+mcFvdFK75y6GCDGfWFO6km8I1fynU7WwKp37/FIKawjW/BpvCY/zufSw1fwYUGd3HUhNSoILUfSw1IQHDsQxpfSw1v0ZAfSz1bN4ajUaj0Wg0mmBBO5YajUaj0Wg0mmDhj3QsOek0J4b+r+C0BFw0Go1Go9FoNN8I3LEMBUSIYCmvL+ISJqz/L/3ne1iNfeStC8EEy2KZfPWc0c+DDt379+/k/cr/Rd8Pnt/O1g4fP3zQfU80Go1Go9FozAjUseRkoXyReqeO7dGlc0fcu3PnO8eR3/ly9U4d28nCd79yQtx/CsvgO7g7d+qA/v16y3tfea49e3ajZrUqaNO6hbyT8/+VOeQwegsLC3lns+FA8prOnz+HurVroHGj+njw4H6w/FaNRqPRaDSav4FAHUu+L3PH9q1YsmghFi2YjymTJ4qz6St7+O4dRo0crvZZJMvlSxeCxdljGdeuXcXihQvk3M7OTuLEPX3yGLdu3cT5s+fw6ZOdupbgb82nU/lBOa3Lly3F5k0b5dz8zbymt2/e4NKli7h44SLevH79f3NsNRqNRqPRaP40AvXKTM7Ut4zcrp07cPDgAcniETpVa1avVs7kJflO2Fzud/4iZhr5nlgulpaW4rj5h7GfpaWVlGNkA42sIZ3aunUbYMWqNVi7YSOSJ08hr+sy4PVEiBDB51x+s6sGPL/5fvxsfk1sen/46CE6d2yPvr174sOHD4gYMaKcv1jxkli3YRPWb9qM3HnyygvqDXiNvFajXLlPflrLeR5uM+4Dfyc/++zvB79l+r1WjUaj0Wg0mt+FMEMU3p+/g/O1rV2zBs+ePZVmYVdXVzx5/BgVK1dGpEg2uHHjOnr36g4XZ2eECR0GXl+9UKhwYeTNl1/ef2w4RXfv3BGH9Mrly3j8+BHixIkDa+WoGe9INva7c+c2Dh7Yjzu3byFSxEh48uQx9u3dI85U0+YtYGNjg5cvX+DN61fi0MWJG0cdZyFl8HhbW1ucOnkSZ06fws2bN9Tar4gbN57MzWVM10ln8/Pnzzh69AjOnT2DK1cuS5/NGDFiiuPGazp18gQO7N+Ls2o7Hb9oUaPh3fu3iB8/vjTJ8x7QyYweI4b0AWXZdILd3T1w8eIFHD92DNeuXoWbmyvixYsvjiD34V86qdu3bZXfyveYMzO6f/8+5ZxflDLjx08ILy/TfTGOu3jhAk6qa2Km9M3bN4ge3XTe//LVchEsTM6+fvOOJiTAumgZwULeRObh6Smyr9H8jXDOVup3vnmHr+zVsq4JCL6lycrS5IOZE+gE6R9sP6Fqlco4cfwYSpQqhadPnuD+vXsYOnwEOnXphnatW2L1qpWoWbuOcn7O49HDh+g/cBC69egFD+X40UljH835c+fg7du33qUCuXLnxuChw5E7dx5pbqfgLlgwD9OmTJamZpI6dRqkSZsW27ZuQeTIkXHs5GkkSZIMM2dMkywi1+3eewApU6fGV+VgnThxHEMGDcCtmzelTELHr269BujZu7eqKBFkJPkl5fgN6NdXrtdwzOiUZs2aDTPnzBVHsF7dWjhy6JBsM0iQMCF27NqjHMI7qFOzujiozFwWLlJUzkdnc5A6/3HlsDo5OckxkWwioVy5iug3YKAqN55kVHmdlcqXFSe5QcPG2LljO54+fSL7x4gZEyNHjUHVatXl+7t3bzFk8CDs3rnDp0yWkT5DBowaMw558uQVZ/TfhiKjJ0jXhBT0BOmakAJ1u54gXRNU/vEE6UmTJkOXrj3k84L586S/5ebNm5AsWXK0adNWncB3szOdtRXLl2HEsKGS6ezZqw9mzp6LMuXK4dzZs+jerQtevHgu2cgjRw5j1Ihh4lQy29mxcxckVI7c1i2bRdC/CfZX5dCZmsfDKscudJjQct57d++iY7u2kiVMlz4DWqnrqVylKpyVMzZj2hTMnT1LHDI3dR1TJ0/C+XNnkTNXLixYtATzFy4Wp5HZyelTp0jmsX79hqhZs7ach9fXrHkLdOvWAzaRbMSZIixPpj1SHrudnR3at2uNPbt2Ik7cuGjWoiUaN22GSBFtsHbNKvRQv9XR0VH25XE8B7Omc2bPVM5zGik/SZKkkr2kc81+q8zE7t65ExvWrZXs7tjxEzFPXWuBgoXkd44eNQIuLi660ms0Go1Go/ltCLJjyabn8hUqoFjxEnj+7JlyGIfAVTk2rdu2RZKkSX2yhITpUXt7e3EMSf2GjSSTWbdefcyeMw/p06fHnVu3cOjgQeU4Anv37IaToxNSpkqF6TNnYfyESViyYiWqVK0mxweYUlXQr2IzO5vIo0aLhnHKAZs+Y5Y4jHQw2RT+8uVLcW55jenSpUfL1m0wavRY1KhVW/2miihbtryUdfv2bTg7O6Ne/QbKMWwq65hZbNe+oxwTLXp0n2ZqAzaVM6N7/tw5cUIHDhoqDvScufPRs3cf2Wf/vr0yEMnoM/rV+xf16tMXK1atxWy1b4tWrWXd6zevxQnl73Jzd5N1Xzy/ILK6jgL5C2DwkGGYNGUamjdvKU63RqPRaDQaze9CkB1Lry9ekrHr0rU7rKytxdlhU2zduvXh4fHNqSRscn79+jWeP38m348dPYoGdeuopTY6tm8rjh6hs8XBNy9fvJDvKVKmQpw4ccUpjWgdEfny55f14n36SyhxFlkOyZA+ozSff/r0SZq5Bwwagms3b4uzyUwhB+C0Ug4iB/2sWL4cDerURoWypbFu7Wo5nvB3urm5iSNK6Ly5uLrIdy9/roP5wqtXr8jnRIkSSzO/w+fP0nSdN18+yYaShw8eyl/y1cvUJzNbthzSpM59EyZKJFlYOpTMQvK8bGZPnDgJPn78gDatWyJblowYNLAfPNQ9Y19WDvrRzqVGo9FoNJrfhZ8aXuzu4Y48+fKiRctWyJIlK3r26YtINjbKGfOdxTOhHB5vn8fO1lYG4jx9+hSPHz1GqtSpkTNXbuWIJTIN4KF3pmB7vQEdQy/lgAUFw7kKGy6sT9Mw17Hp2SJCBOW8hVefTc5uw/p10adXDxlAw/PmzV9ABtH44H0tP4NxfmYvjQE3XNhUbmQpPTxM2Udz6CAa/Tzp0KqD1CfTBbDvZJo0abFj91506dYdmdX9jho1Kk6eOIHePbqjZfNmcHRwkPNpNBqNRqPR/A78tFfCbBubYw8fO4FChQr7mm7HgINpokSOgmjRo8n3Nm3b4fL1a7hw+SrOX7qCPn37i3Oav0BB2R7ZJrL8feXdZM3R2eFklPdHWR8YzI4mSphIPr9580ZGbbNPIqcM2rZlM1q3aIY5c2ZJJvDY0SPSl5KjqvcdOIj1Gzdj0uQpyJUnrxwfEOwvymbugPozMlNJ6EBz0nbjLUSPHj7A61evZFuihKZ9fgYOlmK/yzbt2uPk6bPYtfcAWqt7Sa5fu4r79++LM6vRaDQajUbzO/DzjuXXr+JMGn0W/UvxMQvJQSxsyiUzpk/D0sVLcOTwYSxetAAtmjVB65bNcfrUKWmeLqgcVJZz4cJ5TJwwTvpMThg7RgbTkIAHqHyV/pzFSpSQ5vnbt27KIKCdO3dgzeqVGD1yhIxaN94YZPQDZabwxo0bMjXQlMmTsH7Nt6ZwA8Nh48CcNatX4fDhQ3B1cVbX4vuWfVFOdBH1OxMkSKAc29cYPnQwdu3ahW1bt2LyxAnSrJ4+fQakz5TRZ3qlH6J+LpvFN23cgKKFC6Bpo4YyhRHvPZvxCZ1dOuB09DUajUaj0Wh+BwJ1LOnIfPlicsbMB+eYQ59Pmn69273Z95Kf2JTbuk07lC5TDm/fvlHOZFOULV0C7du2kfkmixUvjtp16srI5goVK6Fy1Spy/OyZM1ClYnlMnjQBuXLnkaZkOmcmByqUzCFHeD1sKqeTmyNHTvTu00+crVUrV6B29ariuN67dxc5c+aSjB+vkRnSdOnS4bO9PZo3bayup6Q4n6lSp/EpU+0ozdOpUqVC9hw5ZB0dxHZtWqnf8U7t5f07lZMoi9rOwUvDR41BrFixZd7NWtWroE6t6jhz5rRyBJNj1JixiBc3ns8xpmZ+L7lX4kVKeZ5yjexzymZxri1ZurSMxj996iSqVamI4kUKSjM++4tyQFTyFCnkOI1Go9FoNJrfgUAnSOeE369ev5Y5I5lVzJghk+EH+cBs4hevL3j37p1MfF6kaDGkEIfnCyJFioSy5crLvIvRokVD4iRJxNHr0r27DAJiudyPk6+XKFEKsWLHkonXc6h9ho0YhSLFismUQZkyZUbxkiWlOZrT9NDRzJI1G4qqc7HJm84t58QsWbI0YsaMKdeRUR3Trn0H9OnXXwYE0dHlNZRQ+4QLH072y5cvv8wHmS59ehnhzsFIufPmlX6LbMouXbosYsSIARt1ndmzZzdlYJVf+fmzPTJmzCTOMcuk88n+kHSQEyRMgKhRo8kgoiZNm2PEyNFIrbbx/LxXnPLos/0npFP3hMfHih1bug5wNDqzwLzuosWKS9/QWLFioVLlKpINjRw5ioxwL16iJIYOH46q1WpIeXRG/wv0BOmakAR1gp4gXRMS0BOka4LKL02Q7ujsqpSol8wdycygf/0pBSV4lsoRovLlPuaTdlMo2QzNzKM4Qmqdp9puyjh+e3MMt3HuxrBhw4izZJyLTieP4dt9uD/LknVqH2Y7jcvn8TJHpNrOH0t4Dl6L+Xk4iMdCVRpeK0d5cyJ3Hssyub8xGpxwH2ZBWa5xPq6jg0v43VfZaj/Oq8nfQOg083f4Pr8yUJaW8pnn4j6E52C5fn+X+TUQ45p5nLHPvw3PqydI14QUWMv0BOmakAB1u54gXRNUApogPXDH0skVDk5OWrA0vtCOpSYkoR1LTUhBO5aan+Efv3lHo9FoNBqNRqMJDO1YajQajUaj0WiChUCbwrnl69dv/QM1GoNQoVVMouVDE4Jgf2eqy0BUpkbzV6BlXRM0QilZ+b6rRKCOpZu7p1r0qF+NbygwVt6jwp1dv3+jkEbzt0HlaWUZAZwpw83D0+/kGBrNX0OYMKFhFcECLq7uMipcowkIDpS2tjINZjYnUMfSwckFDo568I7GNxSZqJEjiVzY2evBO5q/GypIDt6JHsUGjs7OcHLWg3c0fyfU7TJ4R+l3Gbzj6qZlXRMgHLwTI5rpzYnm6FHhmp+GIqNHhWtCCoZjqUeFa/52fBxLPSpcEwT0qHCNRqPRaDQazf8V7VhqNBqNRqPRaIIF7VhqNBqNRqPRaIIF7VhqNBqNRqPRaIIF7VhqNBqNRqPRaIIF7VhqNBqNRqPRaIKFwKcbcnaFh6eXTEHg7u7/RNjhw4eXWfrd3Nxkv39COFUWh697eHjI8m/CKRXChQuPL1881aInhQ0MPmc93VDAhAkTRuqFf7CeeHl9/7aicOHCyV/KfYQIEfyd4sPT0ySbFhYW3mt84+7uLvuwLC7cl+vM4bE8h3ENrLthVZ3zu5/mG3q6ocDhvaBc+XdPKGuUSb9Q7iijrA/8Sxn0C2WUcmnYGL+wXJbPbTw/9ZJfO2RerwzCh7dQx36rA5pv8N7p6YY0QSWg6YYCdSw5+fWBgwdhZWWFXLlyf+dwsdJevHgRH96/R968eWFlbR0k59IwuubGjMrh1q2buHP7NpIlT45MmTJ7b/n/w4rj4PAZG9atQ/YcOZEla1btXAYCn7F2LP2HTuWzZ09xSdULc4XMjwxccufJiyhRoviqJzSqd+/cUQ6LCzJkyIDDhw/BydHRz/GhkDJlKsSMFQunTp7wXc/UbmFCh0H27DkQP0ECPHzwABcunEeKlCmROXMWn33599y5s0iRIgVixowl6969fYeXL58rmc/mu0yND7wr2rH0H94HFyW3R48egbty6nzui/oTWn1OkzY9kit5+2rmxFHX29vb4+rVK8iXLz9u3ryJx48e+nYe1fHRokYTfXzmzGl8Vvv7rQ9JkyZFhoyZlO52wPGjRxHeIjwKFCzk42SyLrJsHpY2bTpZxzcnXb1yCenSpUfESJG0c+kH3iPtWGqCyi85li9evkbhwgVha2uLjZu3Kmcvi0R6hMbwyZPHqF6lMhwcHbBr9z6kTJXKV2ToH6zs69auwRcVbdaoVVu+c7l+/Rrq1q6JyDaR0aBRI7Ro1Vocl0AuL9igQnv96hUa1KujztsKDRs10RmcQOAz0Y6l/9Cobd68ESOHDRO5plLm4uTkiNev32D33v3Imi2bTxaHsufq6oqWzZuibLnyqFGzFurWqqH2fS3HEx5/9+4dtGvfAZWrVkPH9m2Vof7qU7aHhzseP36MZStWiXPZsUM75TymVIb7Mrp174XiJUrIMzupHNKZM6Zh0uSp4ljy3I8ePUKP7l0xfsIkJEuWTAdU/qAdy4ChjL5SurNJw/pKxs1fpvEV9+7dQ/8Bg9C1e0+RUQPWkenTpuDypUuYv3AxRg4fii2bN0kmkVAuX758gXjx4mODsjudO7bH0ydPfOoDX695RwVijRo3wZhxEzBk8EDY2dmpYMxBOZDp0btffyopWddJ1YVmLVqiePESUuc8Pb+gZ4+uyKMCvIaNGkuGU/MN6gntWGqCyi85li9fvUHJksVx+9YtlC5TFgsXL5UsJQ9hJe/RrQvWrVmNaNFjYOOWbZIJoWPJbd+aNkKp/b3Uek/5a21tjXZtW8PF2RnzFiwSpc0M5rw5s7FyxXJs2LgZUaNF86nwYcOymSQM9YQScOCLijA91TmMy+b1UBEx8uQ5aaT5nes9lCKhQTC2G80m3I+VxVhnilpDyXn4mQu3UwFSGYVmGeo71xnNLyEZ3nvtWAaMIUMGlKPFixZgzepVWK/kO1IkG5/tlP3Dhw5h3NhRWL1mvWRRfGfyw+D9u7eoW7cWevbsjUqVq0iGyIDH79+3F4MGDcCWrTtw8sRxnFDLAmWwpynjzUzouPET4azqW4d2bdCgYSOUKFnKp37x+AH9+6o6GxaDhw6TuqXxjXYsA4f3h4kCA+r/hw/uo3Hjhpg8ZRoKFCjoI9O8b44ODqivgvh+/QegYKHCIpuGPjfua+dOHcRWMAiiTje2U3/bfvwo9aFL127ImjU7unXphLnzF+Dz58/o3rULZs2Zh8SJk2DK5AmSkR82YqScn2WwLu7ZvQtzZs/CkmUrpDXOKFujHUvNz/HLb9758sULdevVl+a1TRs3iMNGx2z/vn3S3NaydRtvwftW8Rlt9uujjGCFsqhRrTKWLlkEry+eokC6dumIfXt24/ixo6hYvgwWzJuDEcOHKCUwEU8eP0K9urUxc8Z0KYvnOX3qBBrWr4sK5UqhTq3q2Ll9m5yPC43ifHX8uDGjsXfPHnW+crivouS9e/egTasWuHrlCtq3a43CBfKhd4/upuYXta6xiq4L5s+DIYMGyjXxmhlRt2rRTIx0hAiW+PDhA2rXrI4Tx49h0oTxKFWimLresti3d6/sr9EEBOWD9YQLZZSGcbuS2yZNmyNatOi+nE4q8v379yJ37ryIHCWq2vbV51guVlaW2K0MYby48VCyVGkJbMy3sx5sVPWyevUaknF88vgxEiZIIOVGV+dyZJO6up6N69epADC6KqOMXJMR+PFaKlepKs2Nr16+Qhjv9RpNUKH2N5dJU9Z+E7JmySqZQfNAnNspazRImdV2OnyUReNY9i9m9v3mjeto1qy5HGO+nY7g/v37lGxHQ4UKlfDm9WtYWkZQ660RMWIkVR9M/SnZAnby+HG069BRrocyT7gtb758qk6Ekgy+UQ80Gk3w8WPHUhmyTJkzo3nLlpg8SUWA794qY+WA8eNGo2KlyqIcjGY9VtI3b14rR7Ae3r59Kw5pmbJlsXDBfIwaNUK207ClTJUaiRInRu269aVvV/78BZEtW3bEiBkTNWrVQrbs2WXfkydOoEWzJkpxWKJBoyZIniIlevfqgWVLFouioAF/8vgJxo8fqyLQmcisrpPGk83aGzasx4RxY5AwYSIxyHv27pam7hHDhyJ58hQoU6Ycli1bon7HGDHONMSnTp3Eq1cv1bnDwM3NVZxKOp+PHj5AKVUGI+h+fXri/v37ouQ0moCgPHFhv8ptW7bA4fNnaeo2N7KUOwY2F1WAlip1KoQJw+poOo4L5fudqkdLFy9CnXr1RP6MbVxYB04o43n96lXUqVtPmrFjxY6Nd+/fS9bI2cUZEa0j4vmzp9i2fSuaNW+BLZs3YvCgAbihDC9lmI4l64jtxw94+PC+9NXUaH4WQyaZ+Wb3is0bNyqd3VgCFa43h45l9JgxYGNj43OcsVDmF8ybi4yZsyBd+gxiW4xtrC8fP37EogULULN2HakPNpFtJKvGxIA0t4cKLWWwBaxMuXJ4//6dyPvWLZt99DxbDBjgsa8yW6M0Gk3w8kPHUlVpuKuK27hJM8SOHQdTJk+Sis0m6g4dO3s3cXzLVjJzaGERHhMmTUbtOvXQqnVb9OrdF5uUoqHTWblyFRlUkDRpMjRs2Ag5cuREsWLFlfOaBXFU+XWVs5kvfwFpqpszZybyFSiAufMXop5yUtkPrF27Dpg5c4b06+H5GC6zE/e06TMxeux4ZSQTioGNGiUK+vYfgAGDhmDoiJFopBzT+/fvYdSYsRgybASGjRglju/5c2el8zfLYmRLg2woMa6rXrMmZs2dr8oaiPETJ8FdOQYPVDlybo0mEGi07Gw/YsXypaiggrDoMXxnKylDDNRYvxIlSSqtA+aEVY4fMz8yKKFAIZ8AjlA+mQldsnghChQsKIEa60yePHkkaz9x/HgZjFaocGEsWbQQhQsXkQFFq1evUgY9MoYPG4qnT56KvFtbWyFe/Ph48eK5d+kaza9BmV69aiUSJEwgCQLzJnJDZp8/e4ZUqVJ7W41vMNC5du0qTp48jtq1a6v647uPPbdv27pFHeeFIkWLibwzKIoVM6bYpYnjxyF9uvS4dfMGbFW9S6s+9+7ZQ7pWMRmxb+8eSVjQaHAg3OvXr3wPONJoNMFCkLwjr69eYoz69O2PpaqCsqm6U+euMrrVb7PejRvXJWPITtNswq5fpxbmz50NF2cn6QPDjA0dPy5UMkafRU7zw7KoLLzUNna8fvH8OUqUKClls18Z98+qlBXU9bDZnEaR5cSLFw8JEyeSZj8aZ14HlUlK5cA6OznBVR1LpRQ5cmTEjRtPleMCZ3U9CRIkVOdUistMeRlwFZsQZVStui4OvqBCclPX8PHjB62MND8kvJK5Awf245UyYAyYvnj6HhhDGbKztZXPbNpjH2QDyvb7d+/EKa3foJEK6mKLrBvQ6bx44YKM8m7SrLmSzFCyPVXqNOjbbwA+2n5Au/YdZRT5g4cPUEed/8jhQ2jStBm6de8h669cvSwZJWZVOZjH9iOv5fu6oNEEBcrss6dPsHnTBjRr3hKRIvoedU15p36nbqceNte73Ea9TfuSLFlyFClSFB7u37L7dFg5iJQOYu06daVrCO0Gm8aZPIgaNSrSZ8iItu3bS1/mjp07KwfzpmQ9u3fvifIVK+HYsaPqPKHVAnX+uHBydJLEiNblGk3wEuS0G+exzJ0nD9q2ay+j6UqVLu2drfQNHbjUqdOid59+6DdgEHorIzd2/CTsP3RErU8jyoCYKrj/FZrrPVTZdCZp9MyjVn72UounGFmaU9MgHL9Gm6NmOQLQgMdxMc/68Di5hAD0ClcbTTFE/qoDtCLS/AjKCPv0zp83V0avxlXBj7lj+CNopDesXyefa9aq5auusWxmOZnRL12mDNJ7NxkS/s2VOzeGDhuBosWKi6GuVbuuNDuyPrH5kMFXnDhxJOAyZJwDImikNZpfhXK5ZPEimfKKgz39sw8BQXm/ffs2du/aifYdO6qyfJsmtpBt2bIZrm6uqFe/gY8dYZ1i0NW9Ry906twFO3fukPPnyZNPObC2iBjRWuSbrW3c18vri1wnm8hpq3TXD40m+AmyY0mnihVywMDBGDRkqDhlhsNlwO0pU6TCsxdPkSBhQmTNmg3Zs2eXfjCTJ06QpnAqEMIpivjZv87TLNsmcmTEiBED58+fk75kbKaOYGkpWUwvZRhN2cagG2qN5t+Ek/1zgJr9p08yOMY/p5L1J2IkG1VxIH0tWX8IszPM7nOwXM2atRElKrOZ3+oaDeLNG9dw8/p11K3XQI4z306jy2XT5g1Sd8ooI8/t7Kts++GD2uMrnj19ikiRInnv7y5ZpGjRo/lcg0bzM1CXs189HUM6fhyE49c+8BtlN5IKbuztP/mSNcr8xg3rkCZNGmTNlsMnUCLcjy1GG9auQbVqNb4bAMfPbsqJ5TzIBw/sR/PmLWV9lChRpU8mj3/y9DEsVF3gdfK6Prz/IDMwsJuJ3+vUaDT/jEAdS1Y3qXTe9Y6f2ZTBxRxjH1bwkqVLI0yoMDKFyenTJ2Xi3P59++DevbvSFE1Sp06Ny5cuKiVwAC9fvlRrTIbR+zSSUYkSNSqaNmuB7Vu3YO7sWTLKj1MbTZo4HpWrVkWSJElMEehX31O70EizSfGLH6eTpZtP0muCWUz5I7A8+S3eCo9ZUfkueR3y9ds+Gk0AiGNoby/ZmyLFiknTnnlfMwPKUuLEiRFVOY6c0ssIuvh3986d+KScvXIVKn3XT42ZoOVLl0ozH7tqmBthwuNZ39avWaOMbAu5Hhr6cuUrYLG6Jk7JwjI4+TSv4dMne+kekixJMlWXtGxrfh7K2KYN6yWgMuaM9Av1b8SIEZExS1Zcu3LFR48yucB+wZR5dtmwtrLypdO5nf0j3757K9Nt+dL3CtYJZt/Zz7JUqTJImiyZ2ChOZcRZErp26Yy9u3ehTLnycixbsvgSg7Rp0/o4mhqNJvgI1LHk3I2M+iJYqujTe505XMdMIg0jBypw3shEiRJh2sxZKnp9g1Ytm8tkzmTa9FkSadKgUTnwTQjctkFFqZzwls1wNjacLoJO3FeZT4+Znh69+ihjuBDNmzbG6JEjZAJpDgYyHDyOeo0cOYqcQ1DrOF0Q39pgQL1hqdYx82Mq3wT3ixzZxmcdr4/r2IxORcmMKZviTb/UpDxjRI9h2kcrI00AmGQjFJq3bIXOnbv6a2QNmFHkjAiXLl6Q/SiLlO1UaVJjxqzZSJggvq/jWTYDr4pVqsggNMqkX1nkd0423bVbD6RR9YzZS9Y7Tq7eu09fGVQxYuRo6WdJrl+7ikSJkyBpcuUAfwn4WjWagKCzlj1nTkybMVP0MWXYP7g+Z85cePHyBT58eC/yS2eP+p/zTZYtW86nmduAx/BtbDNmzkbiJEm+2064T5Uq1WTaLW5nnWHyYcq06ciSJYu0tOXNl1/qxutXL6WbSuEiRQOtmxqN5tcI/F3hTi6w/WQvUZ2RTfELlQIrNaNKw0FjcwcrtzFHJJvgeLxRibmOxzDKDKP25SAHfmdZPNaA5bFclkPDSCNsyWjWe19iGvRjmvvPgE3kpmsKr8owrfOvfOPajXVsEuSE1EYUy9/A8/N6ibEusPsREuB90BOkBw5ll0EX5YUyFhDsO8bsIoOsefMXioNHmaZMsgzKvX+wbJYbkGFkoEfZ5ahXc1iHKLssl/LPbiWdO7WX15i2ads+wPOFZKgg9QTpP4ZBOG9LUGSISQdO4cYJ+zkokzqWsslMo38mifWE03H5bS0z4PPg8axvhm0grAOsS6wrhg1hS8LRI4dlthGNb3jv9QTpmqAS0ATpYYYovD9/h7uHctBUJWWl96euC8w2mt6M8034mFGhLLISs1JTWLnOgN854lqMnHfZPIfxhh0Dfub5OXKV/WPo9FFBmCueb46g9woFO35zPjVzWL7f/Xjt5ut4DCfONSUoTU4t//qgfhTXSUUzKyekwftlGYFGJBRcXLUj4h+8R3T6ftS0zO0xYsaQmRQcHZ2QIWNGqSumJWCHlBkicwPqF2bd/Q5oIyyTb8HieWmsb9y4hhMnjqFjpy7KWf2+X5zG9CyppywtLZRO9JTFl17QCJStwGTWgHqfg8lOnTiBfPkLim6mPLK+BCR+lHXzwZh+MdW377sp8TjKO6+L+oqvneQUXRxZniJlqiBdb0hCZF3ZROp3V3dmfnl/tKxr/IdTglkpveiXQDOWdBqcVDSpxUpjDkUmkrWlOPAOTs7eazW/ipER4KvurCNGlM//BjwvWw2ItAQE4qiGdOhY2kS0grOrm87iBAN0XijvzLz/m5OUU8Y5BR0Hh2p5/x56A+HChUEkpQ+clG5wU065lnRNQLAlJ3Ika+9v3wjUseSGQDZrQjA0rFQ4nPpJ888R5a3u6b9d3wyjoZ/ij2Gfc60Tgw/ez/9Cf/xX5/2TEFlX90jfJU1g0H74F2QH6lgyMuei0ZhDibG2slBCFVqiWo3mb4fNtRGtLUUfurl5MAbQaP466AyECxMGVlYR4OLiCo9Auh9oNGzJiRTx+/mPA3UsHZxc4eDopJWoxhcUmaiRTSP47ez14B3N3w0VJJt8okexgaOzM5yc9eAdzd8JdTsH71C/f+LgHVf9yktNwIQLGw4xon0/eOcHo8KVY+lEx1ILluYbFBk9KlwTUjAcSz0qXPO3YziWelS4JigENCo8yG/e0Wg0Go1Go9FoAkM7lhqNRqPRaDSaYEE7lhqNRqPRaDSaYEE7lhqNRqPRaDSaYEE7lhqNRqPRaDSaYOGHjiVHhPldAiMo+wZlH3P87sM55YJynEaj0Wg0Go3m3+OHjiXf4cr3qfI9rqZ3H3vJ67j4Ki6/zh2nKjDfl5/5bm3TO7dNBGUfc0zvkfWS4wzevn2LT58+aedS80cg9SVChEDlle/t5nv1/YN1LbD6wbL514D7RrC0RLjw4b3XfIPvaTbfl5+5TqP53TBkm7IckPxrNJrfj0Ady8+fP6NOrerIlD4NCuTNhdw5siJ1ymRo3bI5Dh06KA4fjSUN57t371C5QjlkzpAW+fPkRL7cOZAlUzr069tbttF4vVMOoX/79Pfeh+WYE0EplW3btiBn9iy4cOG8KsMCDg6f0aRhfUyZPEkUj3YuNb8zlFFbW1scP3ZU3o3sn7xS7h89eoDr16/5cvoMzp07iwf373+3jd+dnJyk7I8fPvjUxWfPnmHzpo24ce2qWvftGAZnLOvjx49yLJcP6rirV67oeqT5rQijHElnZ2ccPLAf27ZsUfXjkQ6ANJo/hEAdS6+vXnj18iUKFymCcRMmYdSYsRgxcpRsq1G1MqYq546GLJQyUF++eOLVq5coW648xk+cjDHjJqBHzz7YuX07evXsDg8PU7bzpd99evTGDrVPb9mHr0ozGThGqM+ePsGIoUPkGtzd3JVh9IK1dUSMGDUGDRo2EkNpnsnUaH4nDFkeM2oEmjZqoOT56XeZFzp3bm5uGDJ4IM6fPedrOzOVF1VAVbFcGaxbt+a7Y5nhXLxwPmrVqIpryinl/q9fv0KfXj1w9PAh9O7VE6dOn5TMJfe9fPkSJk4YJ/WM8NwMHocMGYgXz59/F9hpNP8FEvC8e4c2LZujU/t2GKbks0a1qjignMyAsvoajeb3IVDHkmaRr6HPlj0HyleoiEqVq6JpsxaYv2gJxo6fiFmzZuDkieMIryp7KNPryJE7dx7Zl85jh46dMWzESBw7chgXLyqjKfsBufPk/bZPpy6yz1Huo4wojScNMp3QkSOGI2bMWEiePIU0mRNu9/T0kGZ0jeZ3ho7e3j17sG3bVkSMGFECML9Qni+cP4cP79+javXqPnJNJ8/Ozg5jRo9CaPXZr9PH7M3FCxewaNFCVXYkeWcryzp+7BhixIyBWXPmo3KVqtilgjYVfcHFxQXz582V+pswYUKpXzxXqlSpkCZNWqxYsUwMukbzX0NZnzN7pmQpd+3dh1NnL6BSpUoYPHCACpxefxdgaTSa34sgWRJmOFxdXWVh0xudvFq1ayN+gvjYvm0bvigjJR6jwt1sX2Zi6BjSobSztfPO4ISCu7u7v/vY2tnKPjSaCxfMx+tXrzBoyFBlWEP7ZCZp/AYN6I8Vy5fq6FXz20LjyAzlrJnT0FEFWFGjRVfOnCk4ModyvX/fPuTMlRtRo0ZV+1DOTYPaZkybgjhx4qBy5SpSZwxYBz4pp3PsmFGoV7+BCrySw105iWz2ZjN4okRJ5fhYsWLhs8Nn2X/L5k2IpJzbsmXLqXoT3sc483xVqlbDqZMnldF+o7OWmv8Uyh+7apw8eQJNmjVHsmTJRX4bNm6Cly9f4NrVK1pGNZrfnF9KUXxVjqSVlTVyZM+JK1cuw0OMnsmzDBcurGRq2D8ydOhQOLB/L9yV85gyVSp4SdbxqziE/u6TMpUoDZa5cME89OzTVzmvCfHF07dBZodu3d9G87tCQ+ju4Y5+/Xojl3IYK1aqDE/v5mdz6Pwxk3j+/FmkSZPG22B+VfXCQrKc+/fvQ7/+A0XWjcCKx3C/McqpjBzZBk2V8ZX6obZznxgxYyrD/F45jqElcLNW9fTFi+fYvHkjmrdohb17dotDeufObQnm6OwmTpQYHz68x8MHd7XR1vynUL4dPn/G27fvkDRZMniogInZ9WjRoiFKlKh48fyFT13QaDS/J/+o7YsG1NXVRTKYdCtplCaMH4faNaujXp1aKFIwP5YuXYIevXqL08j9woQJq/YZ6+8+qVOngf2nTxg1YrgY48KFi8DNzdV0Mo3mD4GB09rVq5WBdEC3Hr2kyZldSvzC+sNBa64qqEqYOIlk/plJfPL4MebMmom+AwaZjCv7Hnsfw7L37d2LSxcvYtCQ4Qir6hP7QhP2c86TOw/u3L6NGdOnY8P6tShQsACWLlmCfPny4+bN69ISQEd06OBBPv0qraytETduPOWAvqBll7I0mv8EJX9u7m5wdnZEpEiRJGAiYZWc0rn0rx5pNJrfi192LL988cKbN2+QOHFiyT6aqvtXJE2aDClSpkSy5MlRsHBhrFi5WvpaMurkPlQMAe1DQ7t06WJ8/myPzl26i9GTJjtl68KG9f6s0fzGUEZv3riOFcuWKsdvCGLGioVQoU1N2xzpyv6SBlxna/tRnMaYMWJISwCd0CmTJyJHzpyorIIr1hvWCx7HDD8HyE2ZPAFdunaT/pGsT6FDmfpXsn6lTZcOPXv1wYMH99GkWQvEj59QOZo3Ua9+QxzYv1/6WPYdMBBRlZG+cvmiBHrMiMaKHRsfP9j6GHKN5j9ByR9n/7C0tIajg6NPoMOgy97+k3zWaDS/N0F0LFXlZgVXC40hDdy9e3dx6tRJFC1WwuTwKYXAjGTNWrUxdtxEjB4zDiNHjUG+/AVMGRtvgxXQPjSgnI5o8cKFePr0KRo1qIsypUqgedMmePTwEbp07oQ+vXtKGd66RqP5vVCCSTlft3aNOHbz5s5F44b1MaBfX+n7OHjQAGzduFGyjj6wXnj7cgyk7t29g40b1uP2zZto1rQxWrVohhPHj2P7tq0YOKAfNq5frxzCyzKdUCNVdrcuXfDw4QNMHD8Oi+bPk3LyFyig6tcElC9fQQK1GjVrIUqUKDJ9CwcRsUtKvHjx1HcXqUusn7YfPyKCZQQ5XqP5r2D9oYzGiBEdz58/Q5jQYcTmsE8x+14ys87vGo3m9yVojqUYP9NCx/DIkcNo27oFUqdKjSpVqso6E6FkMI6Tk6MM8uFiTG1iwNHj/u1DhcK+k12790Dbtu1RrFhxlCpVGkWKFEG06NFQqFAh5M2TT0rQaH5LlAxzMExJJbfdevRE2jRpkD59eqRWf60sLZEqZSrEiRdXZN20+1eZPou4uDjzcMSIGQsDBg1GkaLFpN9lhowZET16dMSOHRspUqSUGRX6DxyEjBkzIV26dGpJK2UkTZYUCRMlkjJZn+gsbtmySa6pXPmKsp4B4adPdpJBpdG2VgaccH+uZ1OjNtqa/xK2hMWIEUPJeR4sU0HR+/dvVSAWXoKtOLHjIHOWzGb2RqPR/I6EUgbHO1/yPS9evkbRIoWl71Xq1KlloAHnoYyuosnMmbKIgaOxYxHPnj1FudIl0bN3XxlQYD6KlTCryVGy5coEvA+dRkvLb28RYWbn1q2bqFmtKiZMniKOJq+hRLEiyJkrF8aNnyhOqubfhc87ik1EaYK1++zgvVZjQEMYPrwpK8ksJAfKNKxfF3PnLVSGMYsEUwZs/q5Tu6Zk8es3bCQD4SJEsJRMIp083us2rVrICO9RY8ZJ1tEYuMay3759gxrVqqBv/4EoU7acTMLO+sMMKeez7NuvP7Jkyy7h2JrVq7B+3Rqkz5ARDx88kLlkmbl88uSJ9HmeM28+smTN5j0YT2NABSl9/KJEgqOTC5xdXLUD/n+Ecv1S2Zz27Vrjzes3EvC8UXI+ZNhwVKlS7btkhSb4oL6xULqL+t3ewQmubu5a1jUBEk75ddGj2nh/+0agjqXdp8/YtXsP7Ow+SiaGhFZCli59BjGQptc9cpoTjm51lrko06RNJ30o2bRtjuyjjCKznewH5t8+fqGB5ATOp0+dlPPFiWPK9hw9ekSUTaZMmX9Yhib44TPQjmXQoNw7KGfv3NkzyJ4jB6JGjeZLZhk8DR0ySBxCvoSA2Ri/VfLixQuSbWSW0vxYls3BbeySklbVOzYTcjvrzfPnz/Hk8SPkL1DQe29TfeK8sw8fPkSRIkWRJGlSWbdzx3YsXbIY8xcuhrW1ta5TftCO5b8PX3FqZ2eLw4cOyuwGWbNlQ7p0GZRTqYOe/yfUPdqx1ASVX3IsHZ1d4fnFZKjMYcToN2qk8NH4MQsZUFNFUPbxC+fm4+Agd3c3H4PHJnN+1pmV/wbtWP4clHuTDLt/57SZsvK30LVzR3HsEiRI8F3dMKYb8i9TY5TNbebHGQPf/Gb0uS+38VrYXE66de6ENCrY69Cxk6zX+EY7lv8NtDuUV95r/2yOJvjRjqXmZwjIsQwzROH9+Tvc3D3h5OTsU6mNxT+n0DB8gWU7grKPX3gM37TDvwY0iEF1TDXBD5+FZQQL5dUALq66K8KPMMnwtwFs5rAuxIwZE0+fPoGzk5P0qfQr2/wekLwbZfutU/xuOI7mcJ1RB+nU8v3kfB9z565dpQnev2sM6fCOsKXGSsk8XwDh7qHf+vVvQFkMzOZogh/e8zBhQot+d3XXb7jTBE7o0GFgZal8AT8EmrFktMJFozGHEmNtZaH8ylBwctHzjP5TmBH44vVFmsNtbKKoNf+Oc8fzss8mnUzOGejXOdV8g9mziFaWyti6w83NQ9077w0azV8ENU+4MMpZsIoAF6XbPfy8nESjMYetX5GsLb2/fSNQx5KbjL6VGo05fGMS0fIRPBjNTYFUx/8L/9V5/0SYyaG863ul+ZuhSmAgpWVd8yMMWfFLoI4ls1FOTuxP5L1Co1FQZGwiWSm5CI3PDt9GOGs0fyt0KtnvzMnZVbp/6H5nmr8R6vbw4cKJfndwctHZeU2g8MU1USNH8v72jcAH7yin0sHJSStRjS8oMnrwjiakQAWpB+9oQgLU7XrwjiaoBDR4J4hv3tFoNBqNRqPRaAJHO5YajUaj0Wg0mmBBO5YajUaj0Wg0mmBBO5YajUaj0Wg0mmBBO5YajUaj0Wg0mmBBO5YajUaj0Wg0mmBBO5YajUaj0Wg0mmAhSI5l2LBhET58eHl9D+e04kzr/M715hjbAiKU2sbt3M9YWAbfWewXrjfOFxSMc5uXzeN5nf5dE9cZi0YT3FD2zOWan7nOf0yyakwpS9kNF84kt1zntyzT9/DcUb6zrhh1kcfyM9+tzOPNz8kJ7bndfOpafuZ+XK/R/CommQ3nI7PmMukfhlwasmjsb8gj9bYhk0bZRh3xWx+M42S+UbNz8jjjevwS2qxeaDSa4OUHXtVXVcEt8PjRY4wdPQr58+ZC3lw5kCNrZgwc0A9PnjxRldxUkakIdmzfhupVKuHVq5e+DBphhR89cjgyZ0iLfLlzomDePFJO7ZrVcO3qVVEAhH+tra1x4/p1lClVHDOnT4OFxfcvOTeH5168aCGyZs4g11cwXx7kyp4VBfLmxsL58+Dq4uJTPgmvylu9agUypk+NFcuX+VJSGs0/hbLOOtClc0cUL1oI+fLkRK8e3fHJzs6XHBrwrS7jx43BgvlzRda9vL5gzeqVKFWiKIoXKYTSJYvj5IkTUi6Pt7e3w7Ahg9S2giiQLzdaNm+Kly9Ndc7DwwNjx4xC/Tq11Pk74fXrV7Key/v3b9GxQztVnx8hjCorrJL7O7dvy7W5uDhr51LzS1BuGMgsXbIYpUsUU/JaDO3atsLtW7dEzvzCoOj4saPo0L6tyCvl+saNG2jSqIHIe9UqFbFy5Qp4fvGUZAQdwx3btqF82VIoVbwoGjduiNOnT8lxlOudO7ejQd06aNygHk4cPybreU08bsTwodi6ZYvoeK5zdXXFgH59ceXSJa33NZr/E4E6luGUw3b50kXUqlEVBw7sQ7PmLTBw8BC069ARly6cR6XyZdT2Cz6V1sHBAc+fPxdl4ddI8fvrV68QycYGPXr1Rr+BA9G7Xz9V0d3QqEFd3Lt7V5zY9+/fYdKkCWjapCEuXbyIT/afvivLL9zO4756fUWHTp3Rb8BA9B84CEWKFsWggf2xbNlSUUCEhtnZyQl79+yBp4cn9u3dA2dnZ38Nvkbzs1COWA86KQfu+bOnGDxkGAYNGoL79+5izOiRYuzM5Tls2HB4+PAB9u3bi6LFiqvjwyinchWGDh6ERo2bYuToMShQsCD69e2FBw/uy/H9+vTBkcOH0LffAAwfMVIZdU+1rpfUu7NnTku9mT5ztrxBY82qVSL7POfSJUuQMmVKpEqdGl88PWVJnSYN3r17q+rDXjH4Gs3PwsB+966dEhy1aN1ayeQohFFy3KtXd3y2t/9Ot3p6emCJckJz5coNG2UPuE/Hdm0QJWpUjB0/ETVr1saYUSOVjB+GlaUVLikb1KtnN1SuWg2jxoxFsqRJ0bNHN7x5+wYfP37A4oUL0KFzZ9SuUwczpk+Dk6OjCtAi4PSpUxJElSxZUhxf1p3IkSMjUeLE4gRrNJr/D4F6Ux/ef0C3bp0RK3YsbNy8FW3bd0TVatXRvmMnrFq7HsmSp8DQIYPh7u5O706MV6jQalH//MNLVezk6pgaNWuhWvUaaNSoKRYuXqoi0y/YsH6dMrJhsGnjRmxUn2vVqoMsWbMpJeTpfXTg0KmMGy8uqteooZaaSsnUEyVVvERJHFROMZ1HRr80steuXpFMzYBBg1WkfB137tzxcTw1mn8C68Dnz/ZIniIlxoybiHLlK6Bu/QZoqoKys2fPmOTQzLGk0T186BBSqv1Tpkql6pKbBFsMvlq2ai3y26dvP3FAb968Ic5j1GjRMWrsOFRRdbFK1ero2LmrbLOzs8OtW7eQOUsWcRgLFCyEx08eyXmuXbuG69euokHDxnJOXgMNbYQIEaQubtq0Qa5bB1ian4FyRB19+tRJZM+eA82btxKZ7dylq2ToX7584Uu3soWLuvftm9coXaaMyOCjx4/EQWzfoRNKliqFJk2bIXfu3CpAuqDkMZQkMeLFi4927Tqo4KsEOnXuAgsVBD188ABvXr8RJzJHjhwoUKCQ1I+Pth/h5OSEVatWoGGjxogRM6ach9DBLF+hIh6rc7JVTOt9jSb4CdSK0FhRCfTu0x9RokSFizKKbEpgRBgxYiSMHTceHTp2NlVa74obGDSnrNgsgwub3yJFioTYsWNL1oQOaqXKVbBtx26079RZHE1DIQQJX5fxVY6l0oscOYpJgajvVIS7VHSdImVKlC1XHvHjJ8CmDeuUAtMKRvPPoXzHiRMXkyZPVUFUcnz69AmvX78WpzJNmnTS1G0u0x6eHjh4cL8EURbhLeT4Vq3bilPJzCeX06dPS91JnCgxLC2tMGbseGV488Belf3h40ecPH4cSZIkkewPm9HFaVT78y/7VbKuzZ41QxxI7sNWBZ6HTiT/ZsueHY8fPTQ1kWtDq/kJKMtsemYg9fjxY9y/fxeOyj6cOHESkW0iI6Zy6ry8vLz3ZjN4WBw5clh0MnUv9TPri4UKcC6cPyfyfv/+PZHF1KnTiBwnSZZcyfkHSQI4Ozvh3NlzkqRImDChNJebUDWE/9VC53XVymXSpYqOKLtsMaCjbPN8iRIlgk1kG3Udh+TaNRpN8BKoY8lm8Dhx4iBZsmQ+mUMaI2Y52PydJVt2ZayqB7lyUkmwcvN4LtYRI4qyYF+cNGnSStnx4sUTZ9PN1cXMSfwGj+f5uJgbQX5+q5xT9vPcvm0rNm/aiL59eilF9RktlJFmv0p22H7x4jn2792LQoULI0GCRCq6LiH9cuw/+d//TaP5WWhs6czRoA4c0B85smXB0SNHMHDwYF+OJeXNzvYjPrx7j8SJk/qs9/Bwl780wOxfWbtmdTRs3AQ5c+WWbW5urmJBp02dgrw5s2PO3NkYOmykCv6iiPPKjDyzOSdPnpCmbzZT0qAnT5ECTRs3RId2bTB65AhVjpuchw6ApaWlcgwe6jqg+WmYJWzQqBHixI2DYoULomSxIhg0oB969+uPuHHjSfBCGOgwecBuIWyOpg7ntvgJEkiGvnfP7tJHs6gqI12GDNI65uzkjJIlS0m3pvJlSkt9YDep1m3aiuNJp5R17crlSzh98pTYFWbe2dWpfv2Gqsxu6NyxPdq2boWnT5+KneCSSAVptDs8P69Lo9EEH4FaEWZTrKysEVYZJUJFwE7WVStXRJlSJWTwQLmypSTCNHfyAiK8d6ftZk0ayVKjaiU0qFcHufPmRbUaNaWSczFFuN9Xdq5/+eKF9Enj8vz5Mx+lFSZsGNnGfmwD+veVZe7sWdLsUaBAQXgq5RdOXf/58+fx2dEB5cpVkGuuXaeuRNgHDx5Qv0935tb8cyhXdNQI+31NmDhJMopTp04WI2gYMjpxb9+8ZW4dCRMm8JHlCBEsJahKly69dNfo1q0H1q1bgwsXzkl/NmYtv6q6ULZsOYweNx5FChfBpEnj8ebNGxQsVAgZMmZC21YtZNBa8eIlsWXzJjRSjumqFcvV9sJYumwl7ty5rco7LwFiBHWtSZIkxfv3H3ycW40mqFCeN65bJy1ZAwYOxsAhQ1Ug1BiLFy7Es2fPfGwD93NRMkk5TZkylehzbnukgqD1a1ejYaMm6DdwEEaMHCMZSyYILCzC4+CB/eIE9u7TV/rOd+3aXRIHV65clkRE4yZNMWniBKxcsUya07du3iyO6Js3r6W1YNmKVRJgrVu7RgasEX6n3mdwpR1LjSZ4CdSxZLTJJmoHB0epfGx+iBQxIooWLSaOGftLnj97Fp/sOMDmx5mOr1+9YBM5svR5YUftOHHjo3vP3li6fKVkRg3D6h9sqv78+TNat2qOMipqZWTbuEF902hY5TAyEs6SJSv2HzyCM+cu4tyFyxivDPqMaVNx8sRxyRTRqO/ZvVM5me44fvwYFs6fqxzdY9L8cvDAAckGaSWj+SfQUDLoWbp0sWT5OUChVu06kpHZuX27DMAxDC2R7KTy5YzgjXWABvL2rRvSZFemTFkZjGYTyQabNmxUzt97LFwwV+pCpsyZUbVqNXE+z587J33S6ND26z8Qy1etwey582VQEFsDsmXLIXUlS7ZsiBkrJtgHk4PpKO90Jll/jAymRhNUGBx9+mSH+fPnSf/dFq3aoHTpMhgydDjuquBly+aNkpAwoDPJDCcDJMJm640b1yu5/4ohw4ajVKnSaNWmjWQpJ00cDzs7WyxQZRcrVgKdlUPJ9f0GDJKBlwsXzJdWsMpVqmL5ytVYvZ7nCoebN26gpboOZu1Tp04tzfE5cuWSAZ5eqn5R5t3dPZS8u3snMTQaTXASqDeYLXsOuDi7YNfO7aIIWCkTJ0miKng39O3fD1mzZ0fESJGQNFkyVUEDdgoNPJShzZw5CyZOmoKp02Zg+oyZaNOmrYz8M5raA4Lls4l81px52LV3P3bvO4BFS5d955CyszcVB413w0ZNlRGNhe3bt4nxZIbzkHIgw4ezkKld5syehblzZsHKygq7d+3Ak8eP9fxmmn8E5e6Dcv6mT5kiTW8+U5rQeVRGz4MD3cwwpuuiDFNuudAYb960SYIhwoCOmZYvygg6qiBo9syZuHbtqnezOuvGVzkPnUPKOcuKqAJAjg5ndxbO5sBtvLYvHqa6wiCLWX5CQ8+BP9GiRVPfdGCl+Rk41ZCXzDBA2aP8En62srYWB46fDQzdbOh7Zuspm15fzRw8tT/7XNJppfPHfbmdup1l8Z9VRGtxLmmTuJ3yzzEAixcvQKMmTaR/pci7ujZ1Uri5uCK02bVxsJC1KoN2zfz6NBrNPydQxzJVqlTSP3HihPGm6FBVQGYOaZS2bd2KcaNHo06deuLcmUd+ocOYRl+bL4TVmkaPI/aMhWUFtWKznMSJk6jrSi1L0qTJTMbXn+NZJvuVFSpcRKZgYTaG85lR2W3eth0nTp3FkeMn5e+6DZul7AMH9ktzuUbzq9BJy5otOzJkzCjN0cy2zJ41E31690SWLFmQJm06qQOEfxMmSiQyzG4cNKQ0qPUbNsaKFcswQAVvq1evRM9uXaTfZOXKVZA0eXKULF1a1k2fOgWLFy1A966dECtWbOTMlUfKpPHmYAXO7VqmbHnEjRdP+p4lU8du37YFZ06fxp3bt2QkOusJmyc/fHiH+PHjy3VpNEGFrVDRokeXgWETxo/F6FEjRHa7dukIe/tPSv7KSWBk2vercvgiIpnS2w8ePhB5p2NYuXJVvH75Ch3bt8WqlSukjNkzZ6CSWs9WM2b8Vy5fjv79+spUXL16dMPVy5dl9g+WwXKpv9k8HsHCEsWKFZd6mC59Bpw7dwZnTp3C/n17kFLZDGNezKdPnyBe3LgIb6EdS40muAnUsaQj2Ldff+koPWXSROTKkRUlihZC1kwZ0KdXT5k2qGPnLj7RJw3as6fPULtGdWmuLle6pDRZN6pfV5xIiTyVAxqUisx9mKVk30hzWAaVBhd+NsryUNErMzqcdsiA15MjZy6ZaoXNhLt2bEP+/AWQLFlycWh5PP8y41q0eAmsW7taRvFSWWk0vwLlkfO/shtG2fLlZeosTqXFqX8mTJriK0PCvxxwkzhJUly+fEnWUd45W8H0GbNw8/o1rFi6FG/evMXM2XOVLOcUuef8lS1atpaJoVcrQ5woUVLMnb8A0aNHE8eS8ntbOY5W1laoWLGSKSOk6ka79h3V+cNh/LjRqFe/kfTFZB149uypOjYGkqdMperQj1seNBoDyjB1Lqeg69KtO04cP4qVy5ZJFn3JshXSFG3ocO7LmT7YHePm9esS0PyvvbMAjOLawvAPAUKCBncrlIe0uLsEp7i7u7sUd6dYi1MoxV2KO8WhxYu7azxB3v3PZpIlkCANlNLz0elmZ+7cmd09ds+VoVymSZsW02bOlAz63DmzsXPHDnTt3gMtWrYy9tlL/MyQ4cNxwugDj9+8cUPkPXeePKIPlPeHDx/KKiaNGjcNGBqVK3duVKpUBcOHDUb8hIlQrVoNyaxycg/L586bzwS22hWuKKFNGKPswUZ57h5e8PDyFkfJAdZ79u6Gh7uHZFiyZc+OdKZFSEdG48AWI8e07N27R5TagsfYhV3BtGgP7t8HXx9f5CtQQMoHd2kGhKxj29bNiB07jgSHVpbnTTCLeuzoYdy8eROFTYBo6yK0PRrs/v372LxpoyypcurkSWTKlBnJkid/pT7ey+nTp8Vw8Xx2CfK+lTfD7zZ61MgIGyYsHj1189+r2EPZs7rBKc/8zugEg8oVA821a9bI0AyONeawDJbhuZaO8HzKK88nfM/jfLVggGgv0xzzzDIcw2npGe/JGu/GXTzGhxKMMoHm7Tt3MHzEaHNt20LSSiD8NsKZ3yJG9ChiEz2NTbT/7pVAmaSMWTJLmeRmD4/fu3sXTRo3QJ++A5A9Rw6x9farfPBc6gDl3arLOv4mfbDgAv+U30A9CCMNKetvlmcv1t49uzF0yGDMmjNXFkxXeQ+E3wUfrED7/sTNA97GX/P7VpQ3wR7emC5R/d8F8pbA0htuHh4Bim0bcE0hs42LCWo0qPhcrDYo7C5h65Tn0+HJcilvgbLMujhGRiY4vAWbIw4nddt/JBoydgPyflnG1xgXtlqDws/H4+/TNf9fhd+PBpahA+WTMtesSSPUrlNXug6DOsyPBTM7Vy5dQquWzTBw8FBkzpzlNZ1WNLAMbWjXx48bLZnHwcNGSHf4p7C5VkDasX1bWaqIcwXskyCKBpbK+/FBgaWbMaJu7rbAUlEsKDIu0aKIXDx6ooHl34WNGi6n4uHpLrO3P1W2nA3BK1ev4NzZs/I4SeXNWIFlzOhR4e7paX4nDSz/DmxMccgRH9XIoUmfagINfzNvHx9s37oFOXLm0p6pNxAQWBr7LoGlty7HpAQPA8tYMaL5vwskxMDSh0syaItOCQIFximiI/joTi/vt2eflbfDGePM7Nt3Z38KbF3mHJPGLOnHd+7/Vjij2NnJCT5+vvD1eyb9NsqHw+FLbNi8S29UaMMuc+rZu6xk8l+Ev4uzse9eJqjk45YVJTjYSIzsbFuz2Z4QA0seCeGw8h+GS38QDtJXlP8CtuVu1Cb+66Hp0p8wRAKWdtLvSQkBJrPflNF+5zGWimJBkdExlsp/BRpIHWOp/Begbdcxlsq7EtwYS11XR1EURVEURQkVNLBUFEVRFEVRQgUNLBVFURRFUZRQQQNLRVEURVEUJVTQwFJRFEVRFEUJFTSwVBRFURRFUUIFDSw/Aro8g6IoiqIo/0VCDCwZHzk7OyNSpEgBm5OTs6zM/ylhoMb74CrvwcHHgjk5OX3yoI7PF+ezyC3CmHvk9xPSvSqKoiiKonyJhLhA+oOHjzF7zhzcunVTFk7lc1VdXFxQokQppEiZEs/8+Bi4jwsDRT5XdumSRShurpskSZLXHnvHQG7P7l24cvkyyleohIhOEeV+PzZy3T27cPPGTVSsVFmCyfv37mH0qJEoVqIEihQpimfPnvmX/nLgd6sLpIcMZYMbZZUyTNmgLAT3bGI+L5xl+d2yPB/xyKW5WZ718NWSJdbF8lZdfM9zrWs5OLCuZ3AIZ857zjps+sLHN/KJGkH1x/7ayuvoAulvx3o0KGWSchRUZoPC4yxnyTDl3ZJNyjO/Xz/jX4LXh5embpv/sXSB5bgFXpPn2XTQXraDXlsJhN+LLpCuvCsftEC6l5cXpkyaiJ9nz8aJP4/j6OEj+GXePFQoVxYrli0Vhf7Y0Mg8fPgAI0cMx+VLF994Te7bsmULZsyYbu7ZU875FIQ1BmrL5s2YOWOa/x6bE7p16xa8PD1VIf+j0HHduXMH3bt2hmuRgsiTOwe+790T7m7ub5RNByO/48aOxvRpU+Ho6CjGfcXypShV3BVFCuVHmVIlcOjgIZFznu/h5obhQ4egaOGCyJc3J1q1aIZ7d+/KdelUx40dhepVK6NLxw64e/eO7Od5Dx7cR/t2bXDhwnm5Zrjw4XHm1Cn07N4V3hosKR8I5YYNmTmzZ6K4a2EULpgPVStXxNkzZ95or9nL8/vePWjXphV8fXzk/Ynjf6Ju7ZpG3gsgf77cmDNrpgR+lFvqw5rVK1GqRDHRh1IlXLF/316RX8r2po0bUbtmddSrU8vs3yfX5D1RnIcOHYzlRpd4De7z9vYSXTz+5x+yT1GU0CfECIyK+NL8a9u+PZatXIUVq9dg+87dSJsuHSZPmgB3d3d/BQ4jSkoDYGVlLCdo1WMd9zPH+Wopun+BACV/0/l8ZTc3Azlz6htha9nBlAvj/wxrwuvQ8HB7/tzWorWMDgl639Z9WfA9t6AE7DOv7IKPGNH2EHbed6xYsTBv/q8oXaastLgJy8t9mGtbrWT7+1C+HJi58fDwQHvjNI8fP46OnbqgXfuOOHLoEIYPHyKyYP+7Uw4uXbyINWtWI0/efCLjSxYtRI9uXfBdufLo3rM30qVLj65dOuDixQvmjJfiGFcbR9uqdRt07tLdNLweoocJDinDBw7sw57duzFqzDiRvwULfg3Qgbk/z0HCBAnx9dep8dyU5ZYy9de4cuUKNm/eYGQ/gu2mFOU9oGz9NGUyRo8cgTp166Fr956IEycOOnZoaxpYt+W4Pcwgzpo5A+m/+RbRokfH+fPnJKiMESMGevfpi+rVaxr/MhErVyyXoVerVi5H547tjU0tgx69vkeGjJnQrUsnXDDnPXr0CFN/nIzGTZuh7HflMG7caHh4ekgD7cD+fdJwKly4SEDWMlq06HJvc2bPVvurKB+Jd0rtUSl9fX3hY1qXzs6RkC9ffunypSMT5TT/LVu6RFqbxYoUQtHCBTBi+FC4GwdrGZWFxsEVK1oIxc3xggXyYsb0aRJQ8vywZvtt/TpzvDBcCxeUVumAfn3x5MkTcbTvizjrS5dQqEAe09JdhZbNmyJb5m+RK0dWLF64QIJlBqv8XDNnTJfr8b75yvvk+Qwwf/pxCpo3bexfK8RY7d2zx3y+/Hj44MFr98bPwu+IrfZlSxfLuFAaVta7fNlSdGjbGtmzZjRbJmndv3hpC3aVLwd25z1+/Ahx48XDyNFjZYhEo0aN0aRZcwn4PINksimH27dtRYrkKZAmTRr4GT2js2zTtr1p0HVAmTLfod+AAVKOWR1fXz+EN42ZIcNGoGat2qhRoxY6demKP/74QwLMUydPIlOmTMZpf4NCxqFeNM6XnDx5AkePHELd+g1MXQ5yD3S0zsZxV6xUCUuWLIG721O5jqK8K5bNc/dwR3cT9DVp2gLly1dA3/4DjDw+wvlz58SeWtAfnD17Bjdv3ECp0qWNDXyJO7dvo2DhQhg4eChKlixtGmOdUaBQQezYsd3I6As8uP8ALVq2RvuOnVG6dFn06z8QEZ2c8KeRedrXCI4RkDNnLpF3+qkH9+9Lb9v8X+aJjsSJG09kndDmMwA9d/4vnDxx4rWgV1GUv887eJEwxtn5icIy2/iXMQpr165BiVKlESVKFAnA1q1di+7duqBa9RoYM+4HdO7aXQLHpUsWm2AsojEAxzBoQD80NA524uQf0bJlK4weNQJrVq2UCUE7d25H2zatpEXK83t/3w+LlyzCz3Nmw8E4wfeFxo7jby5euIgJP4yXjM+IUWNQqFARDDcB72UTdHLCDbtjxpj7YEZpwuQp0toe0K+POHpmb548eSxdiRasl10pN67fwPMXzxlPv4LlrGk03d09ZCIPDdnVK1cwYfw4JEuWHMOGjULZsqZlPWaMaU2flu4c5cuBv3f8+AkwccpPSJ06Ndzc3HDPOLqjRw4jZcqUAV3dFmycbd68EZkzZ5FjfN+ydRu0attOegQ4tOPokSNyToKEiSWDQx3Jmzcfnj59arYnOHhgPxIlSij6yCylNHjMJUQezTWou5MnTkTZcuURO3ZskWnWx+O836zZshtdOS8ZUXW0yvtAOaLM9OrdBzVq1hJ59PDwNDJ5AJFMw5pB3XP/XhpCf7F9+zZEjRYNiRMlgY+3N3LmzoMfJkwWm+xhAtQrVy6bBtF50R/qQ9PmLdDeBJse/vrwh/EnlPMkSZPimfFN9FGUZb4SjjFe8Ot86SEqUbIUbt+8KcEv75P1JU2aDNGiRpX7sA96FUUJHd4aWLKrd8TwYciXOyfy5cqBHNky4/Gjh6hfv6Eco2PiJJ5GjZugc5euKFioECpXriJZzaOHD0mAxyyNh9lcXGIgY6aMpmxT9DKtW0djSHi+j48vapmWZfcevUyrszAqVKwI16KuOHb0sDn2oWO/wohhYeu3S7fuKF+xElq1aSPOmoEejYw4bmPYYsaMiSxZspqAt7Vkf8I68GuxZTXtHa2EA+ZeOCkiJHhdZq78T5D7Z7DQo1dvlDOfrXW7dhKYXrh4XibAKF8WdLZ0mBz20LdPb2TPktEEj5vRp98AozOBgSXl65HRJY7HTJosWcB+GUJh/t65YztKlnBFpYrlTaOnPnLmzGmO2XoOKIcTJ4xH7pzZMGniBAwYNEQm1qVO/T8cP/4nrl69It3iX331FTb8tt7U+hJp06ZDg3p10KRRA4w0Om1NfmD3YAQT1F40DS7NWCofAhsvtNIrVy5H0SIF0LRJI7Tv2Emy8NYkT9pBlvvr7FkkSZLUNKptQd0L4wMo8/fu3UO9urWMTGdHlKjR0KRpcwkELX1gIqB0qeIoV7a0JDHy5MmLWHFim8a+N06cOI5Dhw7A0egXG3Pr1q5BnTp10atHNzRr2hitWzbH9evXxJ4zmExsrs8sPv3Ph/kXRVGC461ehIrNrrI+/fqj34CBmDp9Jr75NgNaGUU9feqUlClfoaIEkjQmNatXlfEyBw7sl7FmNAocE1Ovfn1xsiWLF0ONalWQNn16lCpVRoxC8eLFUabsd2jTuqWcX6tGNezYvl1avrw+g7P3x7SkjZOMnyC+uYaPTKZ59uw5vL28TEDpJn/nMi3lSpUro1PHDihRrCgaNqiHXLnyoFChojZjFiq8lMxlggQJxKjKffg9k+DA7elTxgfKFwadF8cEk9Kly6D3932ROHFiTJ/2k5EBnwBHxiDu9u3b4jQT2612wDG7LJMyVSq0adMOzZq1kPFmzNRYy2rxnAIFCkpjLGfO3Phx8iSZwJMvfwGkTJkKjRrUlS7EYsWKS89BnTr1MH/eXGTLlh0zZ/+MY8eOGkd82DjZ8FIfs+n3794LCG4V5Z0xskoZouR8a3xDhw4dJXs5b+7PkgW3soKUaXZR3751A6m+ThUw3py9Q8xkRo4cGXVNA4oyfevmTSxfukR0iZlMnps8xVfG77SWBMDaNWv8M/WJ5VrDhg7GjGlT0bxFS+kJy21s+/379831L2L2z3NNuURYuGAhHPx7iKhbTCxIQOyvj4qihA5vDSy5VAkDyUqVq0gAyZYiu5U58P+H8WPFMU34YRzatW2N9CZYbGYUm5kZdu0xK0fjETVqVAwZOgJr121ATWMEHBzColKF8jLOkE501owZaNyogWRXOBatb/+ByJUnj1zbhq3b7kPU/8VzGi/LWZpX1mM21s2JNuPGT8SKVWtQ2QSYzKyWLVMKy5ctEUNH5Lr+hof/D+dAIxl4J3TE/odDhN1BgU7bnGP+rwbty4OOkEMtOFaXjaL8Jvir36AROnftJktmnT9/XspYcEwlxdKSNwaXSxYvxJkzZ8SRVqxUxTToBpmAMrzZv0hmdv9iAkR2g2fLngM1a9Ux+tIfO3fuwKHDhxApUmT06dsfs+bMk0bgtq1b8VXKlMiaPTuuX7+O7DlySCPnf2nS4uaN65JZp1wyq8RhHoryPtCG+fiPZ7x+7SrSGLmqUrU6Bg0eirv370oAaC/v9Ae+vs9kiBThsX2/78HGjRsksGSCoW27DihnfM000xBj43vF8mU4efIkkiZNioqVq4p/4LCPeUYPKLuVq1TFbCPvvy5cbOqIgqNHj6B5y5Y4d+4c0qZNK0NTcuTMhbt3buGlf4by+bPn0qtgNeYURQk93qnfi+EPYyJuzLJwaQlGU5yc4unpIV1tVavVQNduXWVmK7OE3E+YYfl1/jx07tgB8eLHNwrfCvPmL0S+/PmM09siGZz169fJLOqevXtLxiVR4sSS2bPgZAMaALZ8Q2tMDFvJnJzDLGry5MnRpl1HzF+4SIJjjrHkODUaoFu3b8vnpdHj+7NnT0tQbQWFLMcZ5+zWVxQ6Si43xa7mGyaQo7xyslgEyco4ijOzx5oAxgYQZYrbfKMvK5cvhaPRHU5eYPDnbAJGZlceP36CMaNG4uSJ4zKJh8etrKOXp5e8p7Nltzi7+tgdzmEqzMCzHmbqeZx6Z3V7s0v80eNHcIkRw7zTxo7y7lBenxnbPPWnH7F182YJGBk8UrYiOUWSHqLABrWtPBML4kMM1I9Dhw5h3JhRdtnDl+JbCMf1L1q4QBpbtvHJ1BPI2HxfH1/xC9z4nq+zZs1A7Tp1TeAZVeTdGt/JuuVEA++H2Uw2wqiX9venKMrfJ8TA0qZwYbBp0wb8OGUypk/9EcOGDEa9OrVx+fIlVK9ZWzItHC/D4HLmjFn4efYsdGzXFpcvXTaV27IhHM+yeNECDBk8ULIunIl9/M8/kc4EcTQsyUxgt33bNlP/NPwy92dZquXM6dMy/pDncxkKJxO48R6OHj0c4BDtoVHhDEPLRvA8djdznwX30aHalh6CCWATYZa5l5EjhonhmjFtmnTdpE2XnoWROUtW3L97F21at8IP48ehbeuWki3i4rwvzcaAN0niJDhlHPiUSRNk4DkNI40Y74fX4OW5Vpst+xpo2Hz8yyhfFgzgMmXOjP+lSYOWLZoaeZ5rdGImevXsjnRp0yL1//4X8LvzlV3knNV6Q7KHYaWBUtPo1exZMzF40EDJ1vQ253K8chnT+GJWn7Nf2VCbMfUnmaTApVdcokdHtuzZ/eWOk8y8MWvmdBR1LS7dhexOTJosOdavW4MjRw7LMJavUn4lsujl5S2rPCRMmNASUUV5JxhERjeyV616dZmQOWb0SFkhhDLJB2vwQRGUMcJXBoCUQ06spLwzq89Z2vfu3pN1Lbl6xrixYzDebCVLlpLVFarXqIlff/kFA/v3E33gclv7fv8d5StUkDpYLxtoq1auMO/DiMxTD5mV5yQiyvvmzZuM7qSU8uTa1SuIFz+ejC227k9RlNDBoZ/B/+/X4BMm2JrkE22YIWEwyHFeaYyDHDFyDDJkzChKyW6Gc3+dxZrVq6WrjmMykyVPYVqm4ZA3X34JPOlst23bis2bNuGvc2dlLE29+g0kw5Mtazbpplu1YrksH1GmbFmZye33zE+cKI1RihQpsXr1KsnM5MiVSwyaBQM8roXGFqxrseLiRJ8+dZPlKJgJZZc379M2w/YoihQtahx6UslUMrjduPE3bN2yRYLlZs1bomq16uKgU6RIgZgxY+G39Wtx9sxZGSxeqXJV3Lx5A2XLlZMWdHLzOd3MtThYvEhRV8kUcZFefiecSMFxPEcOH0bxEiURP358uQ8GvEdMoJA3b36k+vrrf2WAGdEEQxLAmO9ceRVm6Sn3lOXVK1fisPmtsxgZ7/V9P3HCzLpYOMuqCDvEEXKmN1+/NnLDcZIcY8blrTgmmOeyTsp9rty5xSHTCXMsM4PTAYOHmsAwkTRgqFN/Gl3lciqcAMH3lDvq7Z49u7Fy+XJUrFgJRVxdjbeHLP+yd+8e1G/YCFEiR35FtxQbDEicIjrC1++ZZNFsmTWFULYyZMiI2HHiSuKA9o/rCQ8cNET228bJ26Bu3Ll7BzuMLyhfqbLso82kbO/b9zs2/rYe5879hZq166Bh46bSzuFQDjbUKO97jfxytY6evfqgYOHC0nvE3+bxo0dYtHAh6jVoKA0k6hHHVbKxP3vmTCQy+5o2by49VbTJCxbMl9U5UqX6WnRGCYRPmaJ99/H1k2y0yroSHJzH4uzk6P8ukBAf6eju6W2Ei4pryzwSS8iY9bNmldJxMfMY6JBs5VmUCk6Y2eS59vXQ4PAcGgYe5zHbcZZjVjGsOd8WuPA4y/GcNwVivD4nycj15NphxIjxvXVfb9pnf198JTxuvWe9vK5133K/5vNybBz32d+7r/+12QqWBaj9lTK4+wjus3zu8LPqIx1DJlAnKDc2OXnT7005YKZlzuxZmP3zPNskCPP9ijxLxt6mH5QdkW0D3/M4sWSQ9do7cEt2uY9lCMtZQSaPM0BidzuX3Lp67RpGjR4r17HKKzb4begjHUOG3wftoGW7g8qsBfdzwlqzJg0xYOAQ0+DKKj08lFXKJvWFXy3r435LVkPSBwuWYXlLx6x7Yln+zf0swwCWy99xHLKtoafybsHvQh/pqLwrH/RIR1pUdh0zw0Yl58a/uVlBJaHCch8V3bb5ynF7xeffPN8qw7+p8ISv1jUCz+cyE4HZMO5nmaCO2ULKm/ONZsh7KgjLW9cgb9pnf1985WYZGr5a17WO8Trs2rbK2N+72Sn7eNy6z5DuI7jPovz7CdQJm2wF93tTnrjEFh3g77/vCQj8bPJo0ylbPYG6RFmy5NE6znrsseqw5JTwPO6z6ZaftDY50WjTpk2oXr2GOBD78oryrlBubDL5Zpm1oAwyw16kiCuWLl0sQ5Uod5RJS19YD/+2ZNGS5bfVzTrsdcy6J0ve+Z7ncjgT1zSOHTtOwDUURQk9QuwKZ7cPs3DaYlGCol3hoQMdG4ducEgEv092Z38qZ8fMz4OHD2W2bd78BfDSrvGjvAq/K+0KDx0o36m+Tg2uF8zuag6Z+hTwN2NgyUCTs8+t3gHlVbQrXHlXPqgrnELFWaSKEhQ+m53mho5W+fuEC2fLVHKIyaeEToO/pW0Yh/9O5TX4PUUIH15sovY0/H0YqHN2uN8/YD/YOyBL4X1iXfu3wEcs0yb4Gd9v39OmKEHhMEnaxaCEGFjSyalgKW+CTsGIjzrZ0ISRugZ3nyfmt2Emh2MA1SaGEv+UvKuehQgbUbYloXS8tRIylBUmRYIS8uQdD2+4eXjIyYpiQZHRyTvKfwUaSJ28o/wXoG3XyTvKu/Jhk3cURVEURVEU5R3RwFJRFEVRFEUJFTSwVBRFURRFUUIFDSwVRVEURVGUUEEDS0VRFEVRFCVU0MBSURRFURRFCRU0sFQURVEURVFChbcElnyOa1g4OjoiUqRIskV0cpKnJrwPLO/s7PzaeXwCAut0jBjRf8/HJ1y4cPIoL0VRFEVRFCV0CXGBdE9vXzx8/ATbt23Fub/+wvNnz5AgUSKULFEKUaNFlQf7vw0Gk/fv38P6detQomRJefA/n1zhYAK8o4cPYfv27UieIjlKlSob8Fi7j4WDgwP++OMYzp87h+/KlX/vAFmxoQukvx3KFhtOAfIcJozoS3DP45bHzD0PfIQa37MOvucrj/EZx4QLFvO4Bd/z+dUvTBn+zcbTC3NdPseV51h1Wsde0VvWZfax3MfUvX8zukD6P0OECBH8/7JhL8vKx4E2QBdIV96VD1og/emTJ2jTsjk6d2iHFcuWYtPGDRjQtw+qVqmA43/+IU7qbdAp3rx5A/37fY8b16/LOQzwLl+6hKZNGmH92jW4ceOGMRgf/9GAvPaunTswdsxICZJVYZSPAWXe7ekT9De64lq4IArmz4OhgwbAx9tbjgWFQeLECT9gxvRp4kxZZuOGDShbuiSKFi6AyhXLi76xHGWWz/We8MN4FCtSyNSdF506tseTx49Er+h4J02cgBpVKqNHt654+OCB7Gedjx49QmdT9uKFC9KwCxcuPM6cOok+3/eCj4+P6oPy2UCZXb16FUqXKIYCeXOjX9/v4enuLvsVRfm8CTGw3L17F35bvw6TJv+EXXv34bfNW7H2t414YgLOYUOHwNfX1pp5k7Jzn+WowoZ1gJOTM8KafWz989ipkyekS3rGnJ/Rvn0ncZpsLYUPHyEgYKUztBythXU9lmc5dtXzbzpKC/trE+scW/3hETGis2RqLFi/fXnCffbX5b3zejzf2s9X2/3ZzrWOB2Dq5HFe2/bWlmmyr1f5wjC/8cuXLzBgQH+sXbMaNWvXQZ269bFq5QqMGT3Sv0igrFFmLl26iBXLlyFHjhzyfs+eXWjXthW+zZARLVq2RtSoUdG+XRtcvXZV5GnKpImY+tMUlK9YCY2bNMUfx46id88eElQeOLAfWzZvwsAhQ/H4yWMs+PUXkT8Hh/CYP28uoru4IGWqVNKwev78Gb5KmQp//XUWW7dsNrL5aoZIUf4JKOPrjd9hIyh33nxo3rIV1q5ejZ49u0vWMqitVhTl8yLECMfb2xtOzs6IHTeOcXjh8czPD0mTJsNP02agkXFodILnzp2TVuVfZ89K0ESlZ1dbxfLfYaVxlhyfaQ9Tp+PHjUWP7l1x5fJlVK9SGZ07dZBzeP6O7VvNuWVRpFB+FC6YDyNHDIOHh6cJxhykrqVLFqNa1UriCJnJyZwhnbyeOP6nCRgjYvq0qWhYv645x0MCON4P/y5XtrSca7tH273wmLu7G2pUr4J1a9eIQSMs06lDOwwZNFD+ZkDaqEFdzJk9Cz17dEOliuXg5eUlWZ4pkyehVIniklmqXauGBONWIBnW1L/ZOPmSxV3N8YJwLVIII4YPhbubuwaXXyjsMqVO7DFy0KdffzRv0RKt2rRFw8ZNsH7dWvPbu4ncWVAOdmzfZvQqKdKmSw9vI1NLFy9Bzhw5MWjwENSoWRuDhgwzcuqOI4cO4v79+1izeiXatGmHDh07SWDZqUtX7Ny5A3fv3sXJEyeQKVNmZM6SBa7FjV6ae2Fj7uyZU9i/fx/q128YIJ+Ua45xLl++IpYsXgQPcw2VS+WfhLrh5eWJhb/OR4kSpdC33wDUb9gIo8eOx+ZNGyUhQZusKMrnS4hehA4qQgRHNG/aGL179ZCxiX5+vsic2Tgt1+LihHx8vHHh4oVXutLosJiFYcbE3okSjhUrVbo0qlarjrjx4qFz166oVbu2BI1HDh9C29at8NVXKdF/4GDTUm2NlSuWo8/3PSULxODSzQSCO7Ztw7SpP6F4iRLo9X1fCfKGDRkswWnefPmwbesWHDlyJCCDeMA41Hv37iKj+TzE3F4AzPJcvnQZT92eIoy/U+U9s3v+zp3bZl8Yec8yAwf0g6/5nA0aNDYOOTJGjxqBX+bNleBh2IhRyJgxI9q1aimfw9k5Enbv2oVWzZsif/78GGiChDbt2mP2zBnmnJ/l3pQvD8pTtKjR0KlzV2TLnkMaNZSZiI4RbWPE7IXPwH2bNm6UQJANI46TLFGyFFq0ai3HvLy9TCAYVsZL+vr6SRlmMYuXKCl1MxB1NDr64vkLGU7i5+uL8BGM4zXXCWv+cUwnG4STJv1g9K4MEiVOjMePH4vuUq6pjzly5jS6/RcuGp21gk5F+Seg/N2//wCnz5xG4SJFJavOBk+qr1PJEJCTJrAM6lMURfm8CDGwTJ4iBVavXY88efLit3VrUf67Msj0bXqMGjkcN29eFyNAJWeQRF23d5nc96bsBx1vmjTpkC5dekSOHAX58uWXQJXM/XmOdNONGjMORYq6olGjxiYgGyrdICeOH5frMWiNEzcuhg4fidZt2qOhKVO3Xn2cOnXSOMxHxgClRnbjKFevXC51EmaKkidPjtSpU8skh1dh97S51zDmXu2cvkM4dh8aJ+u/i067cpWq0nJmUHzn9i1s3bIFbU2wSIf97bcZJHuUKEkSLFmy2Hz2MCZYfYIKlSqjb/+BKFWqDGrXrosirsVw2ASeOqbty4TyzQZTzVq1ESNGDPmNObbxl1/mobSRk2jRookME+oHZfa2kaWkyZIF7C9TtqwJ9nLJ+wimYbRk0SIZ6pEzV24ZPsK6GSASytGcWTORJ29exI+fAKmMjJ84cRy3bt00javDRu5TYMumTSa49ZWGIrP59erUwtgxoySoJNGju5hgNAIumQaiZiyVfxpv05jieMro0aOJPhEOpUqUKDG8vLwD9ERRlM+TEL1I+HDhJRgbOXocVpkA86fpM9CseXPpym7dqsWHdZ0ZR8tMDDdmIZmFkcyMlxcuXrxoHGQ+qZMTHTw9PcWYRHeJjvPnzyGsAzMwL01AGhnx4sU1xz3kPBMbShaGf0cxxypWrIwDBw7gwf370j147NgxEwzW8A8UP8wo0ZglSphI6vD19cEtEwwwCzpzxnTUrV0TDerVQbMmjXH9+jUpS4dftmw51KhRC507djBlaqBOrerYu3uXdGvyM0s0rnxx0BlSFikr/K17dOsiXc5t2nWQ45ZjpJzfvnVbZDppkqQBgR6HoDD7zqEZHHs5deqPkpln48jSFcLyQwcPxJWrV9G7b3+5Xp7ceURO69auhetXr0lmc+HCX1HLNGp++WWudLdPNXq8b9/vpoFzWBqADFaTJUsuuqJOW/nHMSJIMbRvePMveaviqSifPSFGhZs2bZAxguzuZqalYMFC6NajF8aMHS/dvJcuXxLnSAMg3cj+Sk8HFzQbF/D+TYbBHGNGkGNr3oSp3XY+zxXj8tI41cBlJ+gMOZ6R/+iQCxQsKF3269atxZkzpyUQzF+ggC2YMwS5NUECZP8D/FsymK9gu0d2ZfJ6dPoMFtq174Cfpk3HpCk/YvKPU7Fx8zb06v29nDF71kzUr1cbsePERo1atdGlaw9kyZY9oBWuRvLLhUMw7j+4j9Ytm+PmzZsiG8xgWsGjBWWTMGNoQVnn+5kzpsnM8v4DBqF0mbIScBIGgwwuu3XtJMNCfjTylzxZMpF9jokeMGiIjIOePms2du/eKdnQnLly4dqVK8idJw+SmCA2TZq0uH7tqsg65fk59c/TFrAqyj8Jh3tEihxJkgWW3/A08n79+nVEdHIM2KcoyudJiIHl8mVL0bN7N5kwwCCKCs2N2TjCMY90TE+MAXjy5LEp4ywLoTNrx6WKLAPAII0O1Tbjm2O4Xo2omLFhV0fq1P/Drl07TABoG0tGJ3nlymU8evwIKVOmksDubfA6iRInQaHCRWR27LKli2XMWqxYsW0BHe/FvHJRdt4fu6zppJl95DWZDeUSLXfv3AnWgLGeBPETwCmik4z5YRdkggQJES9ePEyZMlHGfzKIXbNmlQQE/QcMhKtrMaRK/bXsN6Gpf03KlwgbHdeuXZOxyS4uLpi/YBESJkrkL2+vqhx1iFiNDZZhw2z82DH4efZsTJg8BdVr1JTgj/sZVHJVhg7t2+Le3btYtGw5vkn/ja1xZepmPWzkxY0b138S0W40atzUJnem7hdG1ySQNHrC8cOEx9hd7xLDhXcg+xTln4DyGzNWLPEFO3Zs92/AR8bFixdE/tOkTSfyqyjK50uIgWX9Bo3w8OEDtGrRVLq/mYH7vncvDOjXV2aScmHzuHHiylhMzqDm+nlDBw9C965dzHkPxQBwo6FgLDVj+k+ytAkNBA2IGAj/MszwNG7SDBfPX0CXzp3w2/r1mPrjFHzfqwcqVKiI9N98I1lKTlLgIG774FT2+fra6mNm0TjNmrXq4Pff9+I3LsxeopSUo9NOmDAhLl+8hOkm+GMwzPFlGTJmkjUERw4fJg69XdvWOH36NE+Q8wgnQDyjMzZ/0ynHih0bdes3kHscNXKErPE5aGB//DJ3LtIbR8/PkzBhInHsv8ybJ7NuO7dvJ2NFreDCrnrlC4GyzSEdjRvWk8CvWPESIodrVq0UGXn06KHIIWEDJ5EJODnZ5tbNm3IuZZgrIYwZNQJly30HP18/6Q7neq9nz57B/Xv30LJ5Uxw8sB/ljV5QnlaburksGMdqUrZYOxt/s2fNkAYWZ5xzchy72zdt/A0nTpzAqZMnkSL5V3I9b9Owun/3HhIY3dC4UvknoV/gxMcq1arL2Houa7dwwXxZeqhQoSJIn+6bN4yTVxTlc8Khn8H/79eIbYLG/PkL4sqVK1hunNuhgwekW6912/Zo3aatzHTl+KxMmTJhp2ldstvcIawD2nfshNt3biFr1uz43//SSCYwfoIEWPDrfMSMGRPZs+eQTOSN6zdQrERJyYYyaxLPlMlogjw+6YeO8sSJP2XCTLuOnWWZImYX2XKlwy5XvoJxxLZ1LK9dvyb7K1WpIhlTOktmHndu34YoUaKgbXvb2DZbNjMxvDw9sWjhr+azFZAxnLzmmTOnsG7tWnHcnI0eIWIExI0dB3nz5Rdjx2WEvv32W1lbkPVwX7pv0ktgvXzZEmzdugUPTDDdvUdPE0yUlHvImiWrBNJLFi/GtatX4VqsGNKkSSNOv6hrsYAA899IRMcIEiDxyQxKIMywsDGx0QRwlL2DBw5g966d2Lt3Dw4fPojcufMitmmUSCPIbM5GTrncEGWKE9nc3NwxeeIPCBc+gugHj/2+d6/Rrx2IHi26THijHnFoyh/HjsmC/zzOtS+/zZAJyZIlM3cRRo5xkljzFq2kkUM4XporJixbugSly5aV8Zfkr3N/YffOnbKsC++Zsq28CnXVKaKjadQ+k8DGahwooQ91gRlLZvm59urevbtlMmfP3r3FV6h8fly4ZBrtuw/nP5jfQmVdCQ6uVuLs9OqSkiTERzq6e3pL4CBdbP6O0AqGGAhaCi6zws1+Lm0iZV/wGeM2A2GVsZybdMn518NuwOfP/VhtALZytvGMFGiWs7+W7TzbPgu+Z7aHY8wIszN8ukjliuVMkNsFdevVC+i+530ySGV9Vh08V7Ko5kYsFbJ93BfyGQg/I8+x7oPw/ni/tu5F22cn1n1Y9Vp18Lj1ddvf/78NfgZ9pGPwUC5s8sLf2k64DZQfe5VjILps6VL8On8eZs2ZK40wmxzZFlq3h+dxY93W3/YErZsNL+qRtY+yyHujPLIOPxMkUVfGjR1p9OUSRo8bLzoctN7/Ovw29JGOnxqbbeW3T3mkTlBuLVuqfBz4XesjHZV35YMe6UiLyiCJ3czSFWyCIf7NzT7A4n6un2cd5xhJnmdfhu+5WU6Lx1guqA+zlfMVA2LVZ1+P7bxXgzLu43lUAJbv831vFClcALHjxJEsoX15Ok7bPQbu47Vkn/89cuO92Rsxlre/D8LPYn1elrXOtbDq5at1nPUEvX/ly4Jywd+aa/BZv721WfJvQVkoUrQoo1FZwJzBn01GbDJlv1H+rLpZJujxoHXz+vb7WIbnWXVwfcyrVy9j04aNsoSWfcNHUf5ZKKO+AbJu2VFFUT5//r19scFA58iu+R49e2PqjFmIY4JLNUjK5wqDRT6ysWu37uB6qkEbLx8XTlzzRr0GDZE1WzZpWCmKoijK3yHErnA6OU4w+DfBpD27+ci/8f7/LXBsBbNsGrSHDvw+qYifNrDkT2ibhf782XN2OvrvVYJifU/8fT71b6QonxLKejgOPaCsaw+GEgIiK8YuBiXEwJID1bmAuaIExdHR9lx4b2+dvBNqmO8Tasg/Szie2MkpgthDPxOEK8qXCofIcPIOx1farxetKEFhD/H7T97x8MZTdw8JIBTFgiLjEs02eefhE528o3zZ0EKGD+eAGC62yTsenjp5R/kyoW3n5B3a98ecvOOtk3eU4OHwrVhvmLzz1sDSzUMDS+VVKDI6K1z5r0ADqbPClf8CVmCps8KVd+HDZoUriqIoiqIoyjuigaWiKIqiKIoSKmhgqSiKoiiKooQKGlgqiqIoiqIooYIGloqiKIqiKEqooIGloiiKoiiKEiqEHFiGAZycnOAcKdIrW/jw4f0LmArChkWECBHkNbRgfY6OEf3fmdvwvwaffKEo/1Wod6KDzs6qC8pnC32GvY94E/QXESMG2ngLnsfzg4Pn0BfYI4s0G53geUGXxmHZoPfi6OgYqv5KUZRXcehn8P/7NdzdPbBs2TLs3LEdB/fvw8ED+3Hw4H6EDxceiRInljWvrl+/hnFjxyJ2nDiIGzeu7PtQaBSo8Pv2/Y4zp08hefIU8v7e3TsYN2YMIkeOggQJE0pZGgfyd66nfDh8MgN/L65zpnx8whsHefzPP7FsyWIcOXIYCRIkQLToLnihj9T8JNAOOUV0lKeR+T17pmv7vQE+SpePBV1qZNTPzw/x4sV/o31mo+j+/fvYuHGDsfHJ5Tx+v7Tpx44dxe5dO5Eq1devfMc8J1z4cFi3Zg1u37mNJEmSSN1hwzrgwYMHWLhgPk4Zn5EsWXKph8d4Dn3Jndu3kdDfb/j6+mLb1i2IGTOmBKLqP16Ha7bSvvv4+uGZsS8q60pw8FHEb3ryTojNNk9PTwwdMhiDBvY3AeZSsy3BpAkTULVyBcycNk0CTA8PD+wygeejhw/EOHwobFlSgLktXrQAUyZPlPr43svLG7t378Tde3el9fn06VP0+b4ntm3bGvBccEX5UmFQuWrFctSqURVr1qzCjOlTUadWDZw+eVLlX/lMCINbt26iV/duaNakkQRvwWUtGfDNnTMbWzZttJUxNt7HxwcrVywT3zJk8EA8DxLQPH78CCOHDxO5X7JoYUAw6uPjjSGDBuD06dPYtmULRo0YLuV5/O6dO/hh3FgJJsOEsfkm+pl169ZixbLlwd6foih/jxAjQSr2y5cv0LlLN2zasg3rftuE/YeOoGr1mhg4sB9OnTqBtGnTYdvO3ciTN5+0UgmVmgrMV+vvV7ruTL1Uah7jNcI5mJbo2rXo2rmTZECdnSPB0b+bhAaGrdNNW7ajePESePbsmbQyt27eghvXr0s9lgHiNaxr2f9tYe23beHMuYFd+KyD5a1zWC//tjdu3B/O7Ocxa2MZ+4DaqofHrHq42dejKO8K5cbtyRMMGzoYlatWw5p1G7Bj115EixZdnKZmXJR/Gtq3Y0ePoGL573D+/DlEd3ER2/4mKM/MVm7evAl16tWX7KKfCfy6dOyAgQP6I0WKr17pImc9V65cMQFnRQlWEyZMJNcjtK9Xr14xPuM6evTohV7f98HxE3/izp3b4j9+mTcXGTJmQr78+Y3f8BNd4fXKla+AVatWSKZT7bKihD7vlGJkcMkAj0Eduw8qVaqEsEYh2TVH5SxWtBAOHjwQEExdvHARbVq3QKECeeFapCB6dO+Ke3fvwcHf2PBcthpr1agmWxXTSp088Qek/+YbRI4SBS9eBD74nkGbm9tTlC5ZDLt378LZs2fRqEE9XLx4AePHjZH69/3+uxgMtlA7tGtjrpsPJYoVQfNmjXHu3F9iqG7evIn6dWujuGthlCrhaupzRb48ObBi+TL/ADKsCW7X4LsypaROXo+G6YUxRrZg0VGu17FtG2z4bT3KlS2FbFkyolWLprhl6ubnJjRey5ctRaUK5eR7qVGtCrYYI0rUiCnvC3Xq4MGDIlfVqtUQ3aA80zlu374ND4yTtm/YKMqnhr6Bw6AmTfkJP8+dj0SJEsm+N0F53mPsuLOzE9Kn/0aSEZTtug0aSKOpcpVqr5xLeY9ifMKQoSOwZOkK8RH0Q4Ry/+jhI/FJEYz9t8bl8/yD+/fjyNHDaNGypbkmx+zbuuuYvcyePYcErOxyt4JURVFCj3fySOHC2TJz3Kignl5eRkH9EClyJDEMJ44fh7ubmygpW6PNmzbC9WvX0b5DJzRv0coEoH+gRfMmePzokThFjtns3bM7Spcpi2HDRyJr1mzS7e5arDhix4r9SmBpojFjKF7g5MmTeGiCWBqthg0bI268eHB1LSbZ1JSpUprg0w1NGjUwgeQ5s68rOnXuihs3bqBbl87w8PCES/ToaNiosezv1r0XEiRIKAFh6tSpJSjcvHmjBKXffPMtevTsjWLFSkiW6Kcpk8UwhQ0bBvfu3cOiRQswf/4vKFmqjKmvCfYbAzZl8iSpg9/NggXzMaBfX3O8lGlB90XuPHnQqUM7CS6Da8UrSnCwMXL79i3RwRgxYojTpCPmmLEwRibva9ZF+YehvU5o7DLtODOFwQWVFgcO7Jcx+ZEiRZJz6Tdy5MiJxIkTG3/y6phtHud4yBw5cyJK1Gjwe2brFSM85mJ0wsv4I3aJe3t7IWwYDp8Ki2lTf0TFipVx+tQptGvbCvN+nuN/FiR5ETNWTOzbt9e8U91RlNDmrYElFfXC+fM4dPAgjhw+LAOu+/ftg/jx45uWX04xIhwDxtYjgytm8+7evSut16rVaqBW7TqY/OM0ExiewOZNGyW4OrB/H7JkyYradeqaoDAVWrVuY+oIb+o/9Hr2xb+nL4J/y5JGpkDBQogaNSq++TYDSpUua1rL8fDIBK0xzLERo0ajbt3aqFa9Klq2aoPbt27hypXLiBotGgoWKoLyFSoiVqxYJiDch959+yFjpswyZnPGtKkmsC2B4SNHoXiJkujRqzfatuuA2TNnmAD1mrkvB3HoKVKmxKjRY03Q3BEdO3WW+g6b+2Yr+smTJ1i2ZIl08TQwwW+uXLnRtFkL5DSvzH4qyvvCoJGNJsaOdNqUQW4RnZzg5OTsX0pR/lkY5DEbyNfgoCx7myDw+rVr+Prr/0nSwIIJCj8/WyYyKJR3W93PTRgYeA59T9IkSWSo1JCBAzFowADjk7IbP3JQJlhxgikb+Qx4V61aidWrVkkDjTXw+nfv3DX1+sh9KYoSerw1sGRrcs7smTLGpaYJ1qpXrWSCuiiYMWu2dH/YGxIaAGYWM2fJIgGgp6eHZCJdXFyQygSQZ86clnIuMWJKNpHBIAPJK1eviPOM7hJd6ggO6v+LF8bImFYtX58/fyaGgUEdMzgTJk2R7o26JmCtV6eedK+7e7jD3d1NzqdhunHjOtq3a42iRVxRx5Thucyk3r592wSsBcRYeXt7Sys4bdq00qDlGB8Hh7DyWePEji2Bqbu7O7xMOd7/gwf35bxHjx7i5s0bWGOMWJ2a1VG/bi3Zjh49imfmXmnsFOV9oD5EM40iqgVlkk6QG3sIKNfqFJV/C5RVHxMgsgEeJ04cCrf/kQ+D9jiCY0T06NUH32bKiFJlSqOWselLFi9Chw6dpCeNvqhBo8YoXbYsDh7YZ86yNcxiGxvu4e4hAavqkKKELm8NLKl4Xbp1x+/7D2LHrj049ucpzP3lV6RNl15amVRUezxMIBecor40hoDGoFTpMhJU1qhaGV06dUCbVi1QuEhR5MqV5z2CL459tN0+M6WXLl3Cd6VLynjLgoUKS7d3+QqVAsbQWGV79egu99B/0GB5TyPD7hV2o7DMq5/G9jnsg10GtAHBtNnPY1aWldlYjsWsUas2xk+YhNFjxmPU6HFYuXotJkycIuUV5X2grCVNmlS6CNn4sXoHrl27ioiOjrbGncqV8h+FyYIYMVxkeFTNWnWxbOkSpEmbDhkyZZKx+czsM3kQM2YsPDdlaa/pn+7cvYsIER1l4qi9fVcU5e/z1sCS65JFco6EmKaFx43jvDij2hpAbQVfhAqbzij10aOHZXkIDqqO6OQMt6dPceHCBXyd+n8SvG3csB6ZjOKzKzpf/gIY/8MkDBw0xDYG0U7J2fUXUmPyyePHMmaTYyA5Y/DFyxcYM+4H1Dat1jx588rsRCsIDB8+nCyZdOjgARPkTTYt5rhyPTppF5cYiBc3ngwq5xpeHCtJg3Tu3FkJJJMkSWqMUvBdPITXiR7dxdQbW9bgTJQkCZIlTy5d/Rs3/oaxY0bK96Mo7wP1LFPmLDKBYeqPkyW7fu3qVVmupWSp0kbmokuDTVE+dxjAOTpGQLSoUaWXJ7TsIW0vEyB/HDuCfb/vRd269WV9V/Ys3bp1S/4+99dZ48ciByQB7t27K8OpIpj7URQldAkxsGSI95JdzqalR+W1tldaeObvZ35+kjVhd3D5ihURLZoLunTqiA0bfsPqVSvQvl0bfJXiK7gWKyZlOPHn6pUrOHv6tIzH5IzylSuWy1hHzu7jxJpjR49i6eJFAV0VzGQyyOMMdTpZLoTLJSPWr1uLB/fvyZhPzpBdsnghNm3agBHDh2LWjOlyvwwqDx06hD69eyJPvnxw9/CQYG+rCUZPnTopBqZZi1YyU324OW+XCTAnT5ogi7JzjCgHldM4cWP3u10sLZ9HPr+5Dgej1zct5zVrVmPYkEHYsWM7Jk+eiFHDhyFRosSyVJGivA/UNTaehgwdLotHWystJDXy37Z9x1d1UVE+A7gmZWDiIRDKKpeS+zZjJvz5xx9iM+1hnPns2XM53+Z9XodDn6xl7SxDzGDRw9MDY0aPQtnvyiGxadSzDvZc3TP+pUnjBti2dSvKfPedXJPnM+OfLn066e1SHVKU0CXkJ+94eGLjpo3IaAxBhowZXzMEVGiOoWSAxlnQCRImkkdr5cyVSyb7cKHzPbt3I/X//ofBxjFykg2V+OHDB5I95Fgbrjl25tQpLFu6FPsP7EOePPmQIUMGGY+5cvlylClb1jhWJ5n4U8gYCq5zFtYYg6RJkmLTxg0ymehbU55d6TQSc2bPkqctMHtYpWo1XDUGpKhrMQlkt2/bCi9zv6xrx/Zt8solkLj8RKqvUyGRuf9lSxdj/do1OH3qNBo2bowmTZoFfNYjR49IcMmufGvfyRMnzOd5iEqVq8g+1pPQBJF8+sT6dbZ6GjdtJlnULylfqU/e+XRQ7zgRgRPVOBGhcpWqqNegYcAsceXjQ13XJ++8HX4vnOGdNVs2aWi/KWjjN8cn6NAuc4a2VUbk3NjgIq6usuqH/UQdwuMZMmSU3qioUaOZPYF1M5Dlk9py5c4j98CyTBjkL1BQusFpn9OlTy/H6AtWrFhmbHtz0SENLF9Fn7yjvCvBPXknjFGqYLXK3dMbnl7eonghKR+Nrn3QycwcRZEtQwolu5x5nBsnxhQumB+NmzRFp85dpGXJ4G7t6lWyXNDK1eskiKWhoNO0rvvaNcw5PGY5Vtt1wpvzbNlDa2yldV3CwNO+TgueK+ebcxg48tosy2vwM1jlLQWzP98617rGu9Tzb4efI3rUyLJiwKOntolRyseHckRd4fdvZcmVjw+1ls42RvQoprHtJTbRsgXK63BZOg4dem7s35ugTWzWtDHy5MmLRo2biE+w4DFu7Kl6E5ZdD8xa2uDvwWO0ufZ6YekM74XHeG/sRfrj2DFMnDTli7HJoQW/D8cI4cW+P3HzkMSByroSHOGNbsV0ier/LpCQx1ganXtTIBaUoA6OTs9SfJ7Lv616OH6xXPnymD1rJhrUq4Phw4agoXkdOmSQLI6bPEUKMSo0AvbXfe0a5rgVVBLbdXzllYrA40GNjH0Qar8ROd9cl2W4j+fxPuzvgX/bvyd8b3+Nd6lHUT4EyrOPccK+pjEWVB8U5XOB9i64oJIwSdCgYSNcunQRHu6vTvak3QwuqCT0JUGDSkL7yvOC6oWlM3zldTjcikOwOA6TQaeiKKFPiBlLTy8fyVra6f3fhsrN7fe9e3DwwAExBJzkkyVrVulCYepdg7DPG/4+UaM4m1ZJGDxx9/TfqyhfLlxuLHqUSPAwNtHLW9c+/LswA8zl2pidZKD5qaC/YWDq7OQscweUV6HrjRDeAVEjO8PNwws+vgzI/Q8qShDCG/2NHi2y/7tAQgwsFUVRFEVRFOVd+XRNRUVRFEVRFOULBvg/BGcwFIhlvOgAAAAASUVORK5CYII=\" width=\"662\" height=\"279\"\u003e\u003c/p\u003e \u003cp\u003e \u003cb\u003eEffect of dapagliflozin treatment on coronary flow reserve and epicardial adipose tissue thickness after 4 years\u003c/b\u003e \u003c/p\u003e \u003cp\u003eWe observed a significant increase in CFR across all patients after 4 years (from 2.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19 at baseline to 2.85\u0026thinsp;\u0026plusmn;\u0026thinsp;0.26 at 4-year follow up, p\u0026thinsp;=\u0026thinsp;0.001) Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003eA. In particular, at 4-year follow up, the dapagliflozin-treated group (group A) maintained the 30% increase in CFR observed during the initial phase (from 3.44\u0026thinsp;\u0026plusmn;\u0026thinsp;0.34 at 4 weeks to 3.18\u0026thinsp;\u0026plusmn;\u0026thinsp;0.44 at 4-year follow up; p\u0026thinsp;=\u0026thinsp;ns between 4 weeks vs 4 years) Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003eB. Group B, the former placebo group, that initiated dapagliflozin after 4 weeks, showed a significant increase in CFR (from 1.96\u0026thinsp;\u0026plusmn;\u0026thinsp;0.09 at 4 weeks to 2.43\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15 at 4-year follow up; p\u0026thinsp;=\u0026thinsp;0.007) Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003eC.\u003c/p\u003e \u003cp\u003eMyocardial blood flow (MBF) at rest was significantly reduced by dapagliflozin treatment in all patients (from 1.16\u0026thinsp;\u0026plusmn;\u0026thinsp;0.06 at baseline to 0.88\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07 mL/min/g at 4-year follow up; p\u0026thinsp;=\u0026thinsp;0.008) Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003eD. The dapagliflozin group (group A) maintained the significant reduction of MBF at rest over the 4-year follow up period (from 1.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.11 at baseline to 0.81\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05 at 4 weeks to 0.78\u0026thinsp;\u0026plusmn;\u0026thinsp;0.082 mL/min/g at 4 years; p\u0026thinsp;=\u0026thinsp;ns between 4 weeks vs 4 years and p\u0026thinsp;=\u0026thinsp;0.008 between baseline and 4 year follow up) Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003eE. Group B showed a slightly reduction of MBF at rest (from 1.11\u0026thinsp;\u0026plusmn;\u0026thinsp;0.09 at 4 week to 1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.11 mL/min/g at 4-year follow up; p\u0026thinsp;=\u0026thinsp;ns) Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003eF. Stress MBF was slightly increased in all patients without reaching statistical significance (from 2.32\u0026thinsp;\u0026plusmn;\u0026thinsp;0.11 at baseline to 2.38\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13 mL/min/g at 4 years; p\u0026thinsp;=\u0026thinsp;ns) Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003eG. No significant changes in stress MBF were recorded for group A (2.41\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2 at baseline to 2.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23 at 4 weeks to 2.38\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2 mL/min/g at 4 years; p\u0026thinsp;=\u0026thinsp;ns)Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003eH, whereas in the group B we observed a significant increase in stress MBF (from 2.085\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23 at 4 week to 2.38\u0026thinsp;\u0026plusmn;\u0026thinsp;0.22 mL/min/g at 4-year follow up; p\u0026thinsp;=\u0026thinsp;0.03) Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003eI .\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWe observed a significant 29% reduction of EAT thickness in all patients (from 0.62\u0026thinsp;\u0026plusmn;\u0026thinsp;0.18 at baseline to 0.44\u0026thinsp;\u0026plusmn;\u0026thinsp;0.11 cm at 4 years; p\u0026thinsp;=\u0026thinsp;0.03) Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003eA. In group A, the reduction in EAT thickness increased compared to baseline (from 0.68\u0026thinsp;\u0026plusmn;\u0026thinsp;0.12 at baseline to 0.53\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07 at 4 weeks to 0.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.06 cm at 4 years; p\u0026thinsp;=\u0026thinsp;0.03) Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003eB. In group B we observed a 19% reduction (from 0.56\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1 at baseline to 0.56\u0026thinsp;\u0026plusmn;\u0026thinsp;0.09 at 4 weeks to 0.45\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07 cm at 4 years; p\u0026thinsp;=\u0026thinsp;0.04) Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003eC. BMI was significantly reduced (from 28.02\u0026thinsp;\u0026plusmn;\u0026thinsp;1,1 from baseline to 25.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.82 kg/m\u003csup\u003e2\u003c/sup\u003e at 4 years, p\u0026thinsp;=\u0026thinsp;0.001). Interestingly, no significant correlation was found between BMI reduction and changes in EAT thickness (R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.0662; p\u0026thinsp;=\u0026thinsp;0.5. Data not shown). Of note, in a subgroup of patients we observed that the initiation of GLP-1 RA at 4 weeks did not lead to a significantly greater reduction in EAT compared to those already on it at baseline, suggesting a prominent role of SGLT-2i in this outcome (p\u0026thinsp;=\u0026thinsp;0.6; data not shown). [\u003cb\u003eINSERT\u003c/b\u003e Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003e \u003cb\u003eHERE\u003c/b\u003e]\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAt baseline, the mean MEEi was 0.323 ml/(sg)\u003csup\u003e\u0026minus;1\u003c/sup\u003e, and no significant changes were observed after four years of dapagliflozin treatment, with a final MEEi of 0.322 ml/(sg)\u003csup\u003e\u0026minus;1\u003c/sup\u003e (p\u0026thinsp;=\u0026thinsp;0.94) (data not shown).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe findings from the 4-year follow up of the DAPAHEART trial demonstrate the significant and long lasting cardiovascular benefits of dapagliflozin in patients with T2DM and stable CAD. The main effects of dapagliflozin observed in this study include: 1) approximately 30% sustained improvement in CFR; 2) a sustained, and even progressive, reduction in EAT thickness; 3) a reduction in myocardial resting blood flow, suggesting enhanced myocardial perfusion efficiency; 4)the stabilization of MEEi, maintaining stable cardiac energy expenditure over time; 5) a causal relationship, as evidenced by the outcomes observed in the placebo group that initiated dapagliflozin at the end DAPAHEART trial. The latter finding reinforces the overall data and provides internal validation within the trial design, thereby helping to isolate the effects of dapagliflozin and strengthen the conclusion that the drug is responsible for the observed improvements in CFR and reductions in EAT thickness. These effects are consistent with the mechanisms proposed in the literature supporting the cardioprotective role of SGLT2 inhibitors. The improvement in CFR is particularly significant, as it indicates the myocardial enhanced capacity to increase blood flow during periods of increased demand, such as physical exercise. In patients with T2DM, this improved CFR could translate into greater protection against ischemic events, reducing the risk of coronary complications\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. The reduction in EAT thickness observed in this study is important because EAT alteration has been linked to coronary microvascular dysfunction and inflammation.\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e By reducing EAT thickness, dapagliflozin likely mitigates the local inflammatory response, thereby improving coronary perfusion and CFR, thus enhancing the myocardial ability to meet increased oxygen demands.\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e Indeed, reduced inflammatory activity in EAT decreases the burden on coronary arteries, allowing for better vasodilation and more efficient blood flow during stress conditions.\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e In addition to the benefits on CFR and EAT, the MEEi was evaluated as a secondary outcome in the DAPAHEART follow up study. MEEi measures the efficiency with which the heart converts metabolic energy into mechanical work. In this study, dapagliflozin helped maintain stable MEEi levels over the 4 years. Although no significant increase was observed, the preservation of MEEi is particularly important in patients with T2DM, in whom cardiac energetic efficiency is frequently impaired as a result of insulin resistance and an increased fatty acid metabolism.\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e In fact, several studies have shown that MEEi progressively declines in parallel with worsening insulin resistance, with higher HOMA-IR quartiles being independently associated with lower MEEi values.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e It is also known that the progression of insulin resistance and microvascular damage over time contributes to further deterioration of myocardial function, especially in the absence of optimal glycemic control. Therefore, the preservation of MEEi that we observed in this study represents a relevant outcome, suggesting that dapagliflozin may help maintain efficient cardiac performance over time, potentially contributing to the improved CFR observed. An additional factor contributing to the observed reductions in body weight and HbA1c during follow-up was the initiation of GLP-1 RAs, which are known for their potent weight-lowering properties and beneficial effects on glycated haemoglobin.\u003csup\u003e\u003cspan additionalcitationids=\"CR39\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e This combination of therapies likely enhanced overall metabolic outcomes in this population. Interestingly, we did not observe any significant correlation between BMI reduction and changes in EAT thickness, suggesting that even though EAT expresses the GLP-1 receptor,\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e the main effect is exerted indirectly by SGLT-2 inhibition\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e. The initiation of GLP-1 receptor agonists (GLP-1 RAs) at 4 weeks in a subgroup of patients did not lead to a significantly greater reduction in EAT compared to those already receiving GLP-1 RAs at baseline, suggesting that SGLT-2 inhibitors may have played a predominant role in mediating this effect. Overall, the 4-year follow up of the DAPAHEART trial demonstrates the long-term efficacy of dapagliflozin in improving coronary microvascular function, particularly through a sustained increase in CFR. This increase, together with the reduction in EAT and maintenance of MEEi, underscores the multifaceted cardioprotective effects of dapagliflozin. These findings support the continued use of dapagliflozin as a key therapeutic option for reducing cardiovascular risk in patients with T2DM and stable CAD.\u003c/p\u003e\n\u003ch3\u003eLimitation and strengths of the study\u003c/h3\u003e\n\u003cp\u003eThis study has several strengths that support the importance of the findings. First, patients were closely and consistently monitored throughout the 4-year follow up period. Despite the use of multiple invasive tests, a significant number of the enrolled patients completed the study, underscoring the commitment of both participants and researchers.\u003c/p\u003e \u003cp\u003eAdditionally, the sophisticated imaging techniques used, namely PET/CT, allowed for accurate and reproducible detailed assessment of myocardial perfusion as well as adipose tissue depots. This enabled the identification of the selective effect of SGLT2i on EAT in just 4 weeks, contributing to a deeper understanding of the rapid cardiovascular benefits of these drugs. However, the study has some limitations. One of the most significant limitations is the relatively small number of patients recruited, which likely contributed to some results trending toward significance but not reaching it. A larger sample size would have provided greater statistical power to detect significance. Unfortunately, the first part of the study (Dapaheart trial) was conducted during the COVID19 pandemic, so a substantial number of potential participants refused to enter the study due to its complexity and the fear of being in a hospital during that period. Lastly, while this study demonstrated a reduction in myocardial blood flow and an increase in CFR, the correlation between these changes and clinical outcomes, such as a reduction in major cardiovascular events, remains to be clarified. A longer follow up period and a larger cohort would help to better evaluate the clinical significance of these findings.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eTo conclude, this study underlines the long-term impact of dapagliflozin on coronary health in patients with T2DM and stable CAD. Beyond glycemic control, SGLT2i actively mitigate the metabolic and inflammatory burden imposed by visceral adiposity on the heart. Our findings underscore the pivotal role of SGLT2 in reducing the progression of cardiovascular risk in patients with T2DM and may have important implications for the management of coronary microvascular dysfunction in this population. By preserving CFR, maintaining MEEi and reducing EAT thickness, SGLT2i provide a comprehensive and sustained protective cardiovascular effect. Future studies should investigate longer follow up periods and larger patient cohorts to fully understand the potential of SGLT2i in cardiovascular prevention strategies, as well as its interplay with other therapeutic agents in this population.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCAD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecoronary artery disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEAT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eepicardial adipose tissue\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eheart failure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMACE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emajor cardiovascular events\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePET\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epositron emission tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSGLT-2i\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003esodium-glucose cotransporter-2 inhibitors T2DM:type 2 diabetes\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eT2DM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eType 2 diabetes\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecardiovascular\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the local ethics committee (Fondazione Policlinico Universitario Agostino Gemelli IRCCS, study protocol code GIA-DAP-16-005) and registered at eudract.ema.europa.eu (EudraCT No. 2016-003614-27) and ClinicalTrials.gov (NCT 03313752). Written informed consent was obtained from all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe corresponding author certifies the accuracy of content, in particular, the names of coauthors and that addresses and affiliations are up to date. The corresponding author certifies that all the co-authors have agreed to all the contents and will notify all the authors when the manuscript is accepted. The corresponding author certifies that all authors have seen and approved the final version of the paper and all are aware of the submission of the paper. All authors consent to publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone of the authors have any competing interests in the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe submitted project was funded by a pharmaceutical company (AstraZeneca) to cover tracer costs.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eF. Cinti, GPS, LL, PI and A. Giaccari designed the trial; A. Guarnieri, LL and MLC described and reviewed PET/CT procedures. LC performed, and DD, FB and F. Crea reviewed, the cardiological procedures. F. Cinti, CM, SG, TM, AS, AA, AP performed and followed up the metabolic procedures. LL and A. Guarnieri performed the PET/CT scans. F. Cinti, CM, A. Guarnieri, LC, LL and GPS were the major contributors in analyzing data and writing the manuscript. All authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMedical writing/Editorial assistance: we thank Serena Rotunno (Università Cattolica del Sacro Cuore). We would like to acknowledge the contribution of the Multispecialistic Biobank Research Core Facility G-STeP, Fondazione Policlinico Universitario “A. Gemelli” IRCCS (Biobank-FPG) who provided the bioresources.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDe Rosa, S.\u003cem\u003e et al.\u003c/em\u003e Type 2 Diabetes Mellitus and Cardiovascular Disease: Genetic and Epigenetic Links. \u003cem\u003eFront Endocrinol (Lausanne)\u003c/em\u003e \u003cstrong\u003e9\u003c/strong\u003e, 2 (2018). https://doi.org:10.3389/fendo.2018.00002\u003c/li\u003e\n\u003cli\u003eHolman, R. R., Sourij, H. \u0026amp; Califf, R. M. Cardiovascular outcome trials of glucose-lowering drugs or strategies in type 2 diabetes. \u003cem\u003eLancet\u003c/em\u003e \u003cstrong\u003e383\u003c/strong\u003e, 2008-2017 (2014). https://doi.org:10.1016/S0140-6736(14)60794-7\u003c/li\u003e\n\u003cli\u003eMahaffey, K. W.\u003cem\u003e et al.\u003c/em\u003e Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). \u003cem\u003eCirculation\u003c/em\u003e \u003cstrong\u003e137\u003c/strong\u003e, 323-334 (2018). https://doi.org:10.1161/CIRCULATIONAHA.117.032038\u003c/li\u003e\n\u003cli\u003eLopaschuk, G. D. \u0026amp; Verma, S. Mechanisms of Cardiovascular Benefits of Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: A State-of-the-Art Review. \u003cem\u003eJACC Basic Transl Sci\u003c/em\u003e \u003cstrong\u003e5\u003c/strong\u003e, 632-644 (2020). https://doi.org:10.1016/j.jacbts.2020.02.004\u003c/li\u003e\n\u003cli\u003eCinti, F.\u003cem\u003e et al.\u003c/em\u003e The effects of SGLT2i on cardiac metabolism in patients with HFpEF: Fact or fiction? \u003cem\u003eCardiovasc Diabetol\u003c/em\u003e \u003cstrong\u003e24\u003c/strong\u003e, 208 (2025). https://doi.org:10.1186/s12933-025-02767-9\u003c/li\u003e\n\u003cli\u003eD\u0026apos;Amario, D.\u003cem\u003e et al.\u003c/em\u003e Impact of coronary microvascular dysfunction in heart failure with preserved ejection fraction: a meta-analysis. \u003cem\u003eESC Heart Fail\u003c/em\u003e \u003cstrong\u003e11\u003c/strong\u003e, 2063-2075 (2024). https://doi.org:10.1002/ehf2.14626\u003c/li\u003e\n\u003cli\u003eZelniker, T. A.\u003cem\u003e et al.\u003c/em\u003e SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. \u003cem\u003eLancet\u003c/em\u003e \u003cstrong\u003e393\u003c/strong\u003e, 31-39 (2019). https://doi.org:10.1016/S0140-6736(18)32590-X\u003c/li\u003e\n\u003cli\u003eScheen, A. J. [EMPA-REG OUTCOME: Empagliflozin reduces mortality in patients with type 2 diabetes at high cardiovascular risk]. \u003cem\u003eRev Med Liege\u003c/em\u003e \u003cstrong\u003e70\u003c/strong\u003e, 583-589 (2015). \u003c/li\u003e\n\u003cli\u003eBeernink, J. M.\u003cem\u003e et al.\u003c/em\u003e Efficacy of Dapagliflozin by Baseline Diabetes Medications: A Prespecified Analysis From the DAPA-CKD Study. \u003cem\u003eDiabetes Care\u003c/em\u003e \u003cstrong\u003e46\u003c/strong\u003e, 602-607 (2023). https://doi.org:10.2337/dc22-1514\u003c/li\u003e\n\u003cli\u003eNiewiara, L.\u003cem\u003e et al.\u003c/em\u003e Impaired coronary flow reserve in patients with poor type 2 diabetes control: Preliminary results from prospective microvascular dysfunction registry. \u003cem\u003eCardiol J\u003c/em\u003e \u003cstrong\u003e31\u003c/strong\u003e, 185-192 (2024). https://doi.org:10.5603/CJ.a2022.0100\u003c/li\u003e\n\u003cli\u003eGalante, D.\u003cem\u003e et al.\u003c/em\u003e Fractional flow reserve (FFR) and index of microcirculatory resistance (IMR) relationship in patients with chronic or stabilized acute coronary syndromes. \u003cem\u003eInt J Cardiol\u003c/em\u003e \u003cstrong\u003e422\u003c/strong\u003e, 132978 (2025). https://doi.org:10.1016/j.ijcard.2025.132978\u003c/li\u003e\n\u003cli\u003eKato, S.\u003cem\u003e et al.\u003c/em\u003e Coronary Flow Reserve by Cardiac Magnetic Resonance Imaging in Patients With Diabetes Mellitus. \u003cem\u003eJACC Cardiovasc Imaging\u003c/em\u003e \u003cstrong\u003e12\u003c/strong\u003e, 2579-2580 (2019). https://doi.org:10.1016/j.jcmg.2019.07.010\u003c/li\u003e\n\u003cli\u003eNesti, L.\u003cem\u003e et al.\u003c/em\u003e Effect of empagliflozin on left ventricular contractility and peak oxygen uptake in subjects with type 2 diabetes without heart disease: results of the EMPA-HEART trial. \u003cem\u003eCardiovasc Diabetol\u003c/em\u003e \u003cstrong\u003e21\u003c/strong\u003e, 181 (2022). https://doi.org:10.1186/s12933-022-01618-1\u003c/li\u003e\n\u003cli\u003eIacobellis, G. Epicardial adipose tissue in contemporary cardiology. \u003cem\u003eNat Rev Cardiol\u003c/em\u003e \u003cstrong\u003e19\u003c/strong\u003e, 593-606 (2022). https://doi.org:10.1038/s41569-022-00679-9\u003c/li\u003e\n\u003cli\u003eCrea, F., Camici, P. G. \u0026amp; Bairey Merz, C. N. Coronary microvascular dysfunction: an update. \u003cem\u003eEur Heart J\u003c/em\u003e \u003cstrong\u003e35\u003c/strong\u003e, 1101-1111 (2014). https://doi.org:10.1093/eurheartj/eht513\u003c/li\u003e\n\u003cli\u003eMalavazos, A. E.\u003cem\u003e et al.\u003c/em\u003e The density of crown-like structures in epicardial adipose tissue could play a role in cardiovascular diseases. \u003cem\u003eEat Weight Disord\u003c/em\u003e \u003cstrong\u003e27\u003c/strong\u003e, 2905-2910 (2022). https://doi.org:10.1007/s40519-022-01420-8\u003c/li\u003e\n\u003cli\u003eGiordano, A.\u003cem\u003e et al.\u003c/em\u003e Obese adipocytes show ultrastructural features of stressed cells and die of pyroptosis. \u003cem\u003eJ Lipid Res\u003c/em\u003e \u003cstrong\u003e54\u003c/strong\u003e, 2423-2436 (2013). https://doi.org:10.1194/jlr.M038638\u003c/li\u003e\n\u003cli\u003eKotzbeck, P.\u003cem\u003e et al.\u003c/em\u003e Brown adipose tissue whitening leads to brown adipocyte death and adipose tissue inflammation. \u003cem\u003eJ Lipid Res\u003c/em\u003e \u003cstrong\u003e59\u003c/strong\u003e, 784-794 (2018). https://doi.org:10.1194/jlr.M079665\u003c/li\u003e\n\u003cli\u003eGiordano, A.\u003cem\u003e et al.\u003c/em\u003e The Adipose Organ Is a Unitary Structure in Mice and Humans. \u003cem\u003eBiomedicines\u003c/em\u003e \u003cstrong\u003e10\u003c/strong\u003e (2022). https://doi.org:10.3390/biomedicines10092275\u003c/li\u003e\n\u003cli\u003eRecio-Mayoral, A.\u003cem\u003e et al.\u003c/em\u003e Chronic inflammation and coronary microvascular dysfunction in patients without risk factors for coronary artery disease. \u003cem\u003eEur Heart J\u003c/em\u003e \u003cstrong\u003e30\u003c/strong\u003e, 1837-1843 (2009). https://doi.org:10.1093/eurheartj/ehp205\u003c/li\u003e\n\u003cli\u003eTaqueti, V. R. \u0026amp; Ridker, P. M. Inflammation, coronary flow reserve, and microvascular dysfunction: moving beyond cardiac syndrome X. \u003cem\u003eJACC Cardiovasc Imaging\u003c/em\u003e \u003cstrong\u003e6\u003c/strong\u003e, 668-671 (2013). https://doi.org:10.1016/j.jcmg.2013.02.005\u003c/li\u003e\n\u003cli\u003eIacobellis, G. \u0026amp; Baroni, M. G. Cardiovascular risk reduction throughout GLP-1 receptor agonist and SGLT2 inhibitor modulation of epicardial fat. \u003cem\u003eJ Endocrinol Invest\u003c/em\u003e \u003cstrong\u003e45\u003c/strong\u003e, 489-495 (2022). https://doi.org:10.1007/s40618-021-01687-1\u003c/li\u003e\n\u003cli\u003ePedicino, D.\u003cem\u003e et al.\u003c/em\u003e Epicardial adipose tissue microbial colonization and inflammasome activation in acute coronary syndrome. \u003cem\u003eInt J Cardiol\u003c/em\u003e \u003cstrong\u003e236\u003c/strong\u003e, 95-99 (2017). https://doi.org:10.1016/j.ijcard.2017.02.040\u003c/li\u003e\n\u003cli\u003eAntoniades, C.\u003cem\u003e et al.\u003c/em\u003e Perivascular adipose tissue as a source of therapeutic targets and clinical biomarkers. \u003cem\u003eEur Heart J\u003c/em\u003e (2023). https://doi.org:10.1093/eurheartj/ehad484\u003c/li\u003e\n\u003cli\u003eSuccurro, E.\u003cem\u003e et al.\u003c/em\u003e Impaired insulin-stimulated myocardial glucose metabolic rate is associated with reduced estimated myocardial energetic efficiency in subjects with different degrees of glucose tolerance. \u003cem\u003eCardiovasc Diabetol\u003c/em\u003e \u003cstrong\u003e22\u003c/strong\u003e, 4 (2023). https://doi.org:10.1186/s12933-022-01733-z\u003c/li\u003e\n\u003cli\u003eVanessa Fiorentino, T.\u003cem\u003e et al.\u003c/em\u003e Depressed myocardial mechano-energetic efficiency in subjects with dysglycemia. \u003cem\u003eDiabetes Res Clin Pract\u003c/em\u003e \u003cstrong\u003e177\u003c/strong\u003e, 108883 (2021). https://doi.org:10.1016/j.diabres.2021.108883\u003c/li\u003e\n\u003cli\u003eMancusi, C.\u003cem\u003e et al.\u003c/em\u003e Effect of diabetes and metabolic syndrome on myocardial mechano-energetic efficiency in hypertensive patients. The Campania Salute Network. \u003cem\u003eJ Hum Hypertens\u003c/em\u003e \u003cstrong\u003e31\u003c/strong\u003e, 424 (2017). https://doi.org:10.1038/jhh.2017.3\u003c/li\u003e\n\u003cli\u003eSorice, G. P.\u003cem\u003e et al.\u003c/em\u003e Effect of Dapagliflozin on Myocardial Insulin Sensitivity and Perfusion: Rationale and Design of The DAPAHEART Trial. \u003cem\u003eDiabetes Ther\u003c/em\u003e \u003cstrong\u003e12\u003c/strong\u003e, 2101-2113 (2021). https://doi.org:10.1007/s13300-021-01083-1\u003c/li\u003e\n\u003cli\u003eLeccisotti, L.\u003cem\u003e et al.\u003c/em\u003e Dapagliflozin improves myocardial flow reserve in patients with type 2 diabetes: the DAPAHEART Trial: a preliminary report. \u003cem\u003eCardiovasc Diabetol\u003c/em\u003e \u003cstrong\u003e21\u003c/strong\u003e, 173 (2022). https://doi.org:10.1186/s12933-022-01607-4\u003c/li\u003e\n\u003cli\u003eCinti, F.\u003cem\u003e et al.\u003c/em\u003e Dapagliflozin treatment is associated with a reduction of epicardial adipose tissue thickness and epicardial glucose uptake in human type 2 diabetes. \u003cem\u003eCardiovasc Diabetol\u003c/em\u003e \u003cstrong\u003e22\u003c/strong\u003e, 349 (2023). https://doi.org:10.1186/s12933-023-02091-0\u003c/li\u003e\n\u003cli\u003eSardu, C.\u003cem\u003e et al.\u003c/em\u003e Effects of Sodium-Glucose Transporter 2 Inhibitors (SGLT2-I) in Patients With Ischemic Heart Disease (IHD) Treated by Coronary Artery Bypass Grafting via MiECC: Inflammatory Burden, and Clinical Outcomes at 5 Years of Follow-Up. \u003cem\u003eFront Pharmacol\u003c/em\u003e \u003cstrong\u003e12\u003c/strong\u003e, 777083 (2021). https://doi.org:10.3389/fphar.2021.777083\u003c/li\u003e\n\u003cli\u003eCherian, S., Lopaschuk, G. D. \u0026amp; Carvalho, E. Cellular cross-talk between epicardial adipose tissue and myocardium in relation to the pathogenesis of cardiovascular disease. \u003cem\u003eAm J Physiol Endocrinol Metab\u003c/em\u003e \u003cstrong\u003e303\u003c/strong\u003e, E937-949 (2012). https://doi.org:10.1152/ajpendo.00061.2012\u003c/li\u003e\n\u003cli\u003eConte, M.\u003cem\u003e et al.\u003c/em\u003e Inflammation and Cardiovascular Diseases in the Elderly: The Role of Epicardial Adipose Tissue. \u003cem\u003eFront Med (Lausanne)\u003c/em\u003e \u003cstrong\u003e9\u003c/strong\u003e, 844266 (2022). https://doi.org:10.3389/fmed.2022.844266\u003c/li\u003e\n\u003cli\u003eDuyuler, S. \u0026amp; Turker Duyuler, P. Epicardial adipose tissue in coronary microvascular dysfunction. \u003cem\u003eInt J Obes (Lond)\u003c/em\u003e \u003cstrong\u003e46\u003c/strong\u003e, 1564 (2022). https://doi.org:10.1038/s41366-022-01125-z\u003c/li\u003e\n\u003cli\u003eIacobellis, G., Corradi, D. \u0026amp; Sharma, A. M. Epicardial adipose tissue: anatomic, biomolecular and clinical relationships with the heart. \u003cem\u003eNat Clin Pract Cardiovasc Med\u003c/em\u003e \u003cstrong\u003e2\u003c/strong\u003e, 536-543 (2005). https://doi.org:10.1038/ncpcardio0319\u003c/li\u003e\n\u003cli\u003eMancusi, C.\u003cem\u003e et al.\u003c/em\u003e Effect of diabetes and metabolic syndrome on myocardial mechano-energetic efficiency in hypertensive patients. The Campania Salute Network. \u003cem\u003eJ Hum Hypertens\u003c/em\u003e \u003cstrong\u003e31\u003c/strong\u003e, 395-399 (2017). https://doi.org:10.1038/jhh.2016.88\u003c/li\u003e\n\u003cli\u003eMancusi, C.\u003cem\u003e et al.\u003c/em\u003e Myocardial mechano-energetic efficiency and insulin resistance in non-diabetic members of the Strong Heart Study cohort. \u003cem\u003eCardiovasc Diabetol\u003c/em\u003e \u003cstrong\u003e18\u003c/strong\u003e, 56 (2019). https://doi.org:10.1186/s12933-019-0862-9\u003c/li\u003e\n\u003cli\u003eAdmani, B., Fahim, M. \u0026amp; Ahmed, H. Semaglutide and weight loss - A concern for diabetics and pharmaceuticals. \u003cem\u003eJ Pak Med Assoc\u003c/em\u003e \u003cstrong\u003e74\u003c/strong\u003e, 1204 (2024). https://doi.org:10.47391/JPMA.10705\u003c/li\u003e\n\u003cli\u003eTzoulis, P., Batavanis, M. \u0026amp; Baldeweg, S. A Real-World Study of the Effectiveness and Safety of Semaglutide for Weight Loss. \u003cem\u003eCureus\u003c/em\u003e \u003cstrong\u003e16\u003c/strong\u003e, e59558 (2024). https://doi.org:10.7759/cureus.59558\u003c/li\u003e\n\u003cli\u003eSwift, C.\u003cem\u003e et al.\u003c/em\u003e Real-world glycated haemoglobin changes among type 2 diabetes mellitus patients treated with a maintenance dose of 7 mg or 14 mg of oral semaglutide. \u003cem\u003eDiabetes Obes Metab\u003c/em\u003e \u003cstrong\u003e26\u003c/strong\u003e, 2111-2118 (2024). https://doi.org:10.1111/dom.15516\u003c/li\u003e\n\u003cli\u003eMalavazos, A. E.\u003cem\u003e et al.\u003c/em\u003e Human epicardial adipose tissue expresses glucose-dependent insulinotropic polypeptide, glucagon, and glucagon-like peptide-1 receptors as potential targets of pleiotropic therapies. \u003cem\u003eEur J Prev Cardiol\u003c/em\u003e \u003cstrong\u003e30\u003c/strong\u003e, 680-693 (2023). https://doi.org:10.1093/eurjpc/zwad050\u003c/li\u003e\n\u003cli\u003eMorciano, C.\u003cem\u003e et al.\u003c/em\u003e SGLT2 inhibition and adipose tissue metabolism: current outlook and perspectives. \u003cem\u003eCardiovasc Diabetol\u003c/em\u003e \u003cstrong\u003e23\u003c/strong\u003e, 449 (2024). https://doi.org:10.1186/s12933-024-02539-x\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":"cardiovascular-diabetology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cvdb","sideBox":"Learn more about [Cardiovascular Diabetology](http://cardiab.biomedcentral.com/)","snPcode":"12933","submissionUrl":"https://submission.nature.com/new-submission/12933/3","title":"Cardiovascular Diabetology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Coronary Flow Reserve, SGLT2i, Dapagliflozin, Type 2 Diabetes, Coronary Artery Disease, Long-Term Coronary Flow Reserve, Epicardial Adipose Tissue","lastPublishedDoi":"10.21203/rs.3.rs-6758884/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6758884/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCardiovascular (CV) outcome trials have shown that sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce CV mortality in type 2 diabetes (T2DM). We previously found that 4 weeks of SGLT2i treatment increased coronary flow reserve (CFR) by 30% and reduced epicardial adipose tissue (EAT) thickness by 19% in T2DM patients with stable coronary artery disease (CAD). However, long-term effects remain unclear. This study aimed to assess the long-term impact of dapagliflozin on CFR and EAT thickness in T2DM patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients with T2DM and stable CAD were enrolled in the DAPAHEART trial, a single-center, 4-week, randomized (1:1 dapagliflozin 10 mg vs placebo), double-blind, controlled study. At the end of the trial, placebo group patients also transitioned to dapagliflozin. CFR and EAT thickness were measured at baseline, after 4 weeks, and after 4 years using 13N-ammonia PET/CT.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCFR increased 34.4% after 4 years (from 2.15±0.19 at baseline to 2.85±0.26, p=0.001) with 29.18% reduction in EAT thickness (p=0.03).\u003c/p\u003e\n\u003cp\u003eBMI decreased in all patients (p=0.001), but changes in BMI and EAT thickness were not significantly correlated (R² = 0.0662; p = 0.5038), suggesting a weight-independent effect of dapagliflozin on EAT.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe 30% CFR improvement seen after 4 weeks of dapagliflozin persisted at 4 years, together with a significant reduction in EAT thickness, possibly explaining CFR improvement. Similar results in the placebo group after treatment, strongly support a causal relationship and underscore the long-term CV benefits of dapagliflozin and its role in reducing CV risk in T2DM patients.\u003c/p\u003e","manuscriptTitle":"Coronary Flow Reserve increase after Dapagliflozin Treatment in patients with type 2 diabetes is maintained after 4 years: a 4-Year DAPAHEART Follow-up Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-09 08:07:49","doi":"10.21203/rs.3.rs-6758884/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-22T18:45:21+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-22T08:30:01+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-22T01:53:48+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-18T17:30:56+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-14T07:46:28+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-13T14:46:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"222613688750513407539096756367094834338","date":"2025-06-05T19:21:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"233602513187464829772023080764135856487","date":"2025-05-30T07:45:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"186754627549926043030806457179470005991","date":"2025-05-30T07:37:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"158323614682203367002408153662032642164","date":"2025-05-30T00:15:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"186876623706857600690762277060252603642","date":"2025-05-29T19:19:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"228317276920538074070264930524020037464","date":"2025-05-29T19:05:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"43569279001628065540387809682305568811","date":"2025-05-28T12:57:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"31907368342561335198881002501588247067","date":"2025-05-27T22:56:33+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-27T18:50:59+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-27T18:38:11+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-27T15:45:16+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cardiovascular Diabetology","date":"2025-05-27T11:13:27+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cardiovascular-diabetology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cvdb","sideBox":"Learn more about [Cardiovascular Diabetology](http://cardiab.biomedcentral.com/)","snPcode":"12933","submissionUrl":"https://submission.nature.com/new-submission/12933/3","title":"Cardiovascular Diabetology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"069b505a-0e8b-482b-a466-37eff7db4a9f","owner":[],"postedDate":"June 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-09-01T16:00:35+00:00","versionOfRecord":{"articleIdentity":"rs-6758884","link":"https://doi.org/10.1186/s12933-025-02912-4","journal":{"identity":"cardiovascular-diabetology","isVorOnly":false,"title":"Cardiovascular Diabetology"},"publishedOn":"2025-08-31 15:57:23","publishedOnDateReadable":"August 31st, 2025"},"versionCreatedAt":"2025-06-09 08:07:49","video":"","vorDoi":"10.1186/s12933-025-02912-4","vorDoiUrl":"https://doi.org/10.1186/s12933-025-02912-4","workflowStages":[]},"version":"v1","identity":"rs-6758884","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6758884","identity":"rs-6758884","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}