Tolerability of endometriosis medical treatment: a comparison between combined hormonal contraceptives and progestins

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Much of the treatment involves hormone therapy that suppresses the proliferation of endometriosis lesions. Objective to compare discontinuation rates of pharmacological treatment with estrogen-progestins and progestins medications. The secondary objective is to evaluate the main side effects of these drugs in patients with endometriosis. Methods this retrospective study analyzed data from 330 patients who attended the Hospital of the State Public Servant of São Paulo from August 1999 to September 2020 and received pharmacological treatment for endometriosis. The data were obtained by review of the files of medical appointments with specialized staff. Results the median treatment time was 18 months, ranging from 1 to 168 months, and 177 patients interrupted the proposed treatment. The combined contraceptives with estrogens and progestins were significantly linked to treatment interruption, with a relative risk of 1,99 (p = 0,005). The most important side effects that resulted in treatment interruption were pain persistence (p = 0,043), weight gain (p = 0,017) and spotting (p < 0,001). endometriosis pharmacological treatment side effects tolerability Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Endometriosis is a chronic inflammatory estrogen-dependent gynecological disease characterized by the development and growth of functional endometrium-like tissue outside the uterine cavity 1 , 2 . It predominantly affects the ovaries but can also affect other organs such as the fallopian tubes, pelvic ligaments, appendix , bladder, and intestines 3 – 5 . The most common symptoms are dysmenorrhea, pelvic pain outside the menstrual period, dyspareunia, infertility, urinary and evacuation symptoms. However, its clinical presentation can be non-specific and with symptoms disproportionate to the extent of the disease, making diagnosis difficult 6 – 10 . Endometriosis significantly impacts women's quality of life, compromising their social and emotional relationships, work, and study performance. It is an important public health issue, affecting 6 to 10% of women of reproductive age, with a peak incidence between the ages of 25 and 35 years 4 , 5 . The treatment of endometriosis includes surgery, medication therapy, and assisted reproductive techniques. As a chronic disease, patients should be monitored for many years and receive individualized treatment according to their clinical status and reproductive desire at each stage of life. The goal is to remove endometriotic foci surgically or suppress them with clinical treatment. However, the best approach has not been defined yet 11 – 14 . The medical treatment aims to induce a hypoestrogenic state of chronic anovulation, creating an inadequate environment for the growth and maintenance of endometriosis implants 7 , 13 , 15 , 16 . The medical treatment is not curative, as it cannot eliminate the endometriotic foci, only making them temporarily inactive during medication use 17 . Among the therapeutic options, we have combined hormonal contraceptives containing estrogens and progestins (EP), isolated progestins (P), antiprogestins, GnRH agonists, GnRH antagonists, aromatase inhibitors, and medications that do not act as hormonal suppressants, such as analgesics and non-steroidal anti-inflammatory drugs 9 . Considering the chronic use of these medications, it is important to evaluate not only their efficacy but also their tolerability, side effects, cost, and each patient's preferences 7 , 13 , 17 , 18 . The tolerability of treatment consists of the patient's ability to tolerate the side effects and maintain the use of the medication. It can be evaluated through the rates of treatment interruption or follow-up losses in clinical studies 17 . It is recommended to start with low-cost drugs, such as combined oral contraceptives and some progestins, and then move on to high-cost drugs, such as GnRH agonists, in cases of low adherence, tolerability, or ineffectiveness 7 . Although widely prescribed, combined hormonal contraceptives have no scientific basis to prove the superiority of this group of medications compared to other classes, and does not appear to be any advantage of any specific drug within this group 7 . Continuous administration of combined contraceptives has been more favorable in controlling pain than cyclical administration. It is possible to perform a planned interruption only to control spotting, which is bleeding that occurs outside of the menstrual period 19 . Regarding ethinylestradiol dosage, low-dose options with 20 mcg are safer, with a lower risk of thromboembolic events 17 . According to some authors, progestins have fewer side effects than combined contraceptives and can be prescribed in various routes of administration, oral, injectable, implants, and intrauterine devices 9,20−25 . Desogestrel and dienogest are 19-nortestosterone-derived progestins widely studied for the treatment of endometriosis and have been shown effective in controlling symptoms 20 , 22 . Symptoms can be controlled by various drugs, many of them with great pain control results, the limiting factors are the side effects and tolerability related to these medications. Adequate monitoring and control of unwanted effects are essential for achieving therapeutic success. Thus, studies that compare drug options, considering not only the efficacy but also the quality of life of patients, are necessary to guide conduct. Objectives This study aims to compare the discontinuation rates of medical treatments for endometriosis with combined hormonal contraceptives and isolated progestins. The secondary objective is to evaluate the main adverse effects related to the discontinuation of these medications. Methods A retrospective study that evaluated the rate of medication interruption by patients attended in the endometriosis sector of the State Public Servant Hospital in São Paulo. The data was collected through forms filed in the specialized outpatient clinic. Patients attended from August 1999 to September 2020 were evaluated. To be included in the study, a histological confirmation of endometriosis and a medical treatment prescription was necessary. Patients with incomplete data for the study, those who were already in clinical or surgical postmenopause at the first consultation, hysterectomized patients and finally, those patients who did not have a minimum follow-up time of 6 months in the presence of medical treatment were excluded. Epidemiological data were collected to trace the profile of attended patients. The time between the onset of symptoms and the surgery date was evaluated. The symptoms questioned were dysmenorrhea, dyspareunia, cyclic pain, pain while evacuating, pericicatrical pain, infertility, urinary and intestinal symptoms. The surgical findings were raised, researching where endometriotic lesions were found. The surgical procedures performed and the staging of endometriosis were also researched. The classification of endometriosis from the American Society for Reproductive Medicine (ASRM) was used as a reference 8 . The prescribed medications for clinical treatment were chosen based on reliable guidelines such as ESHRE’s, on the opinion of the attending physician and on the patient’s preferences 6 . These treatments were verified for the type of hormone and dose. During the entire follow-up, patients were questioned about the symptoms and side effects presented during treatment. The use time of each medication was recorded, and once the patient opted for discontinuation, the reason for discontinuation was also recorded. A new medication could be prescribed, containing the same hormone with a different dosage or a medication from a different class. An informed consent form was applied before data collection. This study was approved by Research Ethics Committee of State Public Servant Hospital and is registered in Plataforma Brasil under CAAE number 36271213.8.0000.5463. Statistical analyzes were performed for two distinct groups, isolated progestins (P) and combined contraceptives (EP). Frequencies were calculated using the information available for each data point. The data obtained were grouped in an Excel spreadsheet for Windows® and were analyzed using the statistical programs Epi Info7® an Open-Epi, online version 26 . Continuous variables were tested for their distribution and are presented in means and standard deviation or medians and quartiles, depending on the normality of this distribution. Categorical variables are presented in percentages, according to the data available for analysis. The variables relating to adverse events and complaints reported during clinical treatment were correlated with the outcome of treatment interruption, and multiple analysis of logistic regression was conducted using the STATA 12.0® program, grouping the adverse events that presented potential statistical significance in the univariate analysis (value of p < 0.25 was used to select variables for multiple final analysis), except those that did not have enough outcome events to be included in the adjusted modeling. A p-value < 0,05 was considered statistically significant. Results As reported in Fig. 1 , we enrolled 392 patients in the study, and after applying exclusion criteria, 330 patients remained for analysis The average age of patients at the time of the first consultation was 37.57 years (+/- 6.27), ranging from 17 to 53 years. The average age of symptom onset was 31.07 years (+/- 8.4), ranging from 8 to 51 years. The average age of menarche was 12.46 years (+/- 1.73), ranging from 8 to 17 years. Out of the total, 138 patients (42.72%) had no children at the time of the first consultation and 40 patients (12.39%) had had one or more abortions. Hormonal contraceptive methods were used by 145 patients (46.17%), 36 (11.46%) used permanent methods, and 96 (30.57%) used only condoms or no method. Three patients were using GnRH analogs at the time of the first consultation. Table 1 describes the most common conditions; arterial hypertension was the most frequent. Table 1 Personal medical history reported by patients at the first visit. Comorbidities Frequency Percentage Cancer 7 2.12% Cardiopathies 10 3.03% Diabetes Mellitus 16 4.85% Arterial Hypertension 43 13.03% Thyroidopathies 17 5.15% Gynecological Diseases 20 6.06% Psychiatric Diseases 0 0% Of the total, 18 patients (5.45%) were asymptomatic at the time of the first consultation and 3 (0.91%) received the diagnosis in surgeries indicated by other hypotheses, making endometriosis a surgical finding. Twenty-five patients (7.57%) did not have data for calculating the time of symptoms. Thus, 284 patients remained, with whom it was possible to calculate the time between the onset of symptoms and the diagnosis. The median time between symptoms and surgical diagnosis of endometriosis was 31.1 (14.13–63.53) months, ranging from 1.03 to 426.13 months, data illustrated in Fig. 2 . Table 2 illustrates the symptoms reported by the patients before starting prescribed treatment. In Table 3 , it is possible to evaluate the main sites of endometriotic lesions described in surgical reports. Table 2 Symptoms reported by patients at the first appointment. Symptoms Frequency Total Available Percentage Dysmenorrhea 266 329 80.85% Dyspareunia 144 327 44.04% Acyclic Pain 144 329 43.77% Painful Defecation 13 329 3.95% Pericicatricial Pain 14 329 4.26% Infertility 61 326 18.71% Hematuria/Urinary Symptoms 8 328 2.44% Constipation 102 320 31.88% Intestinal Bleeding 2 328 0.61% Tenesmus 5 329 1.52% Percentages are calculated based on available data. Table 3. Location of endometriotic lesions. Percentages are calculated based on available data. According to the available surgical descriptions, 74 (48.05%) capsule resections, 40 (25.81%) oophorectomies, 37 (23.87%) cyst drains, and 13 (8.44%) cauterizations were performed. We obtained the description of the pelvic endometriosis stage according to the American Society for Reproductive Medicine (ASRM) classification for 248 patients, distributed as follows: 21 (8.47%) cases of minimal endometriosis, 26 (10.48%) cases of mild endometriosis, 90 (36.29%) cases of moderate endometriosis, 103 (41.53%) cases of severe endometriosis, and 8 patients with a diagnosis of abdominal wall endometriosis (3.23%). Thus, 77.82% of the cases were in stages III or IV and 18.95% of the cases were in stages I or II. All patients included received drug treatment according to Table 4 below. These methods were studied according to composition, isolated progestins (P) or combinations of estrogens and progestins (EP) to facilitate data interpretation. Table 4 Medications prescribed at the start of the follow-up. Medication Frequency Percentage Transdermal EP 1 0.30% Oral EP 137 41.52% Vaginal EP 4 1.21% GnRH Analogs 4 1.21% IUD P 15 4.55% Injectable P 73 22.12% Subcutaneous P 1 0.30% Oral P 95 28.79% Total 330 100% EP combined hormonal contraceptives, P progestins. Therefore, 4 patients (1.21%) received GnRH analogs as the first option of medical treatment, 142 patients (43.03%) received combined methods prescriptions, and 184 patients (55.76%) received a prescription for isolated progestins. The preferred prescription form was continuous. Among the combined contraceptives, the most frequently prescribed dose was 30 micrograms of ethinylestradiol, prescribed for 95 patients (28.78%). Among the isolated progestins, the most frequent was desogestrel, prescribed for 87 (26.36%) patients. As shown in Fig. 3 , the median treatment time was 18 months, ranging from 1 to 168 months. Of the total, 177 patients (53.63%) discontinued the proposed treatment. During de follow-up after starting treatment, the patients reported several complaints, as shown in tabre 5. Table 5 Symptoms reported in follow-up consultations after starting the first proposed treatment. Symptoms Frequency Percentage Headache 11 3.33% Persistence of Pain 110 33.33% Spotting 164 47.9% Intense Bleeding 14 4.24% Breast Pain 3 0.91% Nausea 7 2.12% Weight Gain 24 7.27% Figure 4 illustrates the evolution of the patients monitored during the study. Analyzing only the patients who discontinued the use of medication, based on the reported side effects, we obtained headache in six patients (9.84%), breakthrough bleeding in 47 (77.08%), weight gain in eight (13.12%), persistence of pain in 23 (37.72%), nausea in six (9.84%), mastalgia in two (3.28%) and acne in one patient (1.64%). Given the complaints reported and the interruption of treatments, medication changes were proposed. Of these, 67 changes (46.52%) were made to medications in the same category and 77 changes (53.47%) to medications in a different category, as shown in Table 6 . Six medication changes involved GnRH agonists. Of the four patients who started the follow-up with GnRH agonists, three switched to combined hormonal contraceptives and one to progestins. Two patients changed to GnRH agonists, one used EP and the other P, previously. Table 6 Medication swaps after the first proposed treatment. Medication Changes Frequency Percentage From EP to EP 26 18.06% From EP to A 1 0.69% From EP to P 44 30.57% From A to EP 3 2.08% From A to P 1 0.69% From P to EP 27 18.75% From P to A 1 0.69% From P to P 41 28.47% Total 144 100% EP combined hormonal contraceptives, P progestins, A GnRH analog. Source: the author (2022) Of the 153 patients who did not interrupt the initial proposed treatment, 96 received P and 57 received EP. The average follow-up time for these patients was 38.91 months. Among the users of EP, the events that showed an association with the interruption of treatment were persistence of pain, with a relative risk of 1.65 (p = 0.031) and breakthrough bleeding, with a relative risk of 2.76 (p < 0.001). All of this group who reported weight gain interrupted the treatment, but there was no statistical significance due to the low frequency of this complaint (p = 0.1345). It was observed that the highest risk of interruption of EP occurs up to 9 months of treatment, with a relative risk of interruption of 2.32 (p = 0.026). Treatment time above 10 months did not correlate with the risk of interruption. Among the users of P, the events that had a greater impact on the risk of interrupting treatment were breakthrough bleeding and heavy bleeding, with a relative risk of 1.35 (p = 0.032). The time required for adaptation to treatment, and consequently not showing a correlation with medication interruption, was longer for P users. Up to 84 months of treatment, we have a relative risk of interruption of 1.74 (p = 0.04), becoming non-significant thereafter. When the two groups were compared, the patients who received P as the initial treatment had a significantly higher age range (p < 0.001) and had some reported personal medical history (p < 0.001) compared to those who received EP. The multiple logistic regression analysis that correlated adverse events, type of medication, and treatment interruption showed that the complaint of breakthrough bleeding, weight gain, persistence of pelvic pain, and treatment with EP had a direct, significant, and independent association with clinical treatment interruption, adjusted for the complaint of headache, as shown in Table 7 . Table 7 Multiple analysis of side effects, type of medication used, and treatment interruption. Treatment Type and Side Effect "p" Value of Univariate Analysis Univariate Analysis OR (CI) "p" Value of Adjusted Analysis Adjusted Analysis OR (CI) Spotting < 0.001 2.267 (1.457–3.528) < 0.001 2.672 (1.672–4.269) EP 0.016 1.725 (1.106–2.692) 0.005 1.995 (1.237–3.219) Persistence of Pain 0.043 1.619 (1.015–2.582) 0.043 1.670 (1.017–2.743) Weight Gain 0.066 2.330 (0.946–5.740) 0.017 3.227 (1.237–8.418) Headache 0.080 3.994 (0.849–18.778) 0.076 4.440 (0.855–23.060) OR Odds Ratio, CI confidence interval, EP combined contraceptives containing estrogens and progestins. Considering only the patients who received EP, the multiple analysis showed that the adverse events of spotting and persistence of pain and the staging of minimal/mild endometriosis had a significant, direct and independent correlation with the interruption of treatment with EP. Infertility had an inverse correlation with the interruption of treatment. These data are shown in Table 8 . The variables were adjusted for a treatment duration of fewer than 9 months, education level, and complaint of headache. Table 8 Multivariate analysis of the correlation between side effects, education, staging, and follow-up time with the risk of interrupting EP treatment. Side Effect "p" Value of Univariate Analysis Univariate Analysis OR (CI) "p" Value of Adjusted Analysis Adjusted Analysis OR (CI) Spotting < 0.001 4.267 (2028 − 8.978) < 0.001 8.432 (2.632–27.014) Persistence of Pain 0.117 1.769 (0.898–3.610) 0.006 6.388 (1.721–23.714) Infertility 0.136 0.533 (0.234–1.218) 0.010 0.153 (0.037–0.632) Duration of Follow-Up Less than 9 Months 0.041 3.291 (1.048–10.335) 0.067 4.550 (0.8990–23.009) Staging Minimal/Mild 0.155 2.106 (0.755–5.874) 0.026 5.578 (1.233–25.233) University Degree 0.236 0.636 (0.331–1.344) 0.429 0.619 (0.188–2.032) Headache 0.299 2.348 (0.469–11.742) 0.435 2.741 (0.217–34.491) EP combined contraceptives containing estrogens and progestins OR Odds Ratio, CI confidence interval Table 9 Multivariate analysis of the correlation between side effects, stage, and parity with the risk of treatment interruption with P. Side Effect "p" Value of Univariate Analysis Univariate Analysis OR (CI) "p" Value of Adjusted Analysis Adjusted Analysis OR (CI) Spotting 0.057 1.775 (0.984–3.203) 0.024 2.638 (1.134–6.136) Weight Gain 0.073 2.405 (0.923–6.271) 0.211 2.110 (0.655–6.796) Intense Bleeding 0.086 4.062 (0.821–20.104) 0.308 3.443 (0.319–37.174) Staging Minimal/Mild 0.005 5.206 (1.654–16.382) 0.001 8.078 (2.291–28.482) Nulliparity 0.171 1.538 (0.830–2.852) 0.239 1.667 (0.711–3.907) P progestins OR Odds Ratio, IC confidence interval. As shown in Table 9 , the adverse event that had a significant and independent correlation with treatment interruption with P was the presence of spotting. There was also a direct correlation with intraoperative endometriosis staged as minimal or mild. Discussion The medication therapy for endometriosis consists of long-term treatment, like therapies for other chronic diseases such as diabetes mellitus and systemic arterial hypertension. The pain symptoms related to endometriosis cause a huge impact on quality of life and can be controlled with the use of these medications 4 , 5 , 12 . It is natural for patients with endometriosis and pelvic pain to receive medication therapy until there is a desire for reproduction or menopause 4 . Thus, studies like this one, which seek to evaluate the efficacy and tolerability of the medications, are of extreme value. In the most recent recommendations for endometriosis management, we find a trend towards patient-focused treatment, their desires and symptoms, rather than endometriotic lesions, so medication therapy can be implemented without delay, even in the absence of histological confirmation of the disease 4 . Despite this approach gaining strength, all the patients in the present study obtained a diagnostic confirmation through surgery and a large part of them only started to be followed by the specialized sector after the procedure. Given the wide range of clinical manifestations and differential diagnoses, the time between the onset of symptoms and the definitive diagnosis with specialized endometriosis group monitoring is usually long 27 – 29 . This study found an average of 4.8 years between these two events, with a non-parametric distribution, so the median of 2.5 years should be considered. In some scientific articles, the interval described is 6 to 8 years 9 , 10 , 27 . The two most frequent symptoms were dysmenorrhea and dyspareunia, as reported by other studies 5 , 30 . The ovaries are the most affected areas by endometriosis, as shown in this study, which demonstrated ovarian endometriotic foci in 65.64% of the procedures. Definitive surgical treatments, such as hysterectomy and bilateral salpingo-oophorectomy, were exclusion criteria. Among the conservative approaches performed, the resection of endometrioma capsules (48.05%) and unilateral oophorectomies (25.81%) were the most frequent. The two most prescribed drug classes were combined contraceptives and isolated progestins, in their various doses and administration routes. There is no evidence that demonstrates superiority in pain control by a specific administration route. Considering the prolonged use of these medications, the administration route should facilitate treatment adherence and be in accordance with each patient's preferences 9 , 17 . Continuous administration was preferred over cyclic administration for better control of dysmenorrhea. Periodic pauses were indicated only to control irregular bleeding and spotting. Combined contraceptives and progestins seem to have similar effectiveness in controlling pain symptoms, achieving this result in two-thirds of patients 5 , 17 , 21 . According to Vercellini et al., combined contraceptives containing the lowest possible dose of ethinylestradiol and second-generation progestin can be considered first-line therapy in peritoneal lesions and endometriomas. Isolated progestins can be prescribed as an alternative to combined contraceptives when there are side effects, deep endometriosis, and in case of a contraindication to estrogen use, such as a high risk of thromboembolism 7 , 17 , 31 . In fact, the group that received isolated progestins as a first-line therapeutic option was associated with a more advanced age and personal history of chronic diseases. The most frequent adverse event among patients who discontinued the proposed treatment were breakthrough bleedings, present in 77.08% of cases. Breakthrough bleedings were found in both groups and with a direct and independent association with medication interruption. This finding suggests that proper management of breakthrough bleedings may impact adherence and, consequently, therapeutic success. Pain persistence is expected in some patients using first-line therapies such as combined contraceptives and progestins. Some authors report a lack of response to these medications in up to 30% of patients, a therapeutic failure attributed to the progesterone resistance present in the disease's pathophysiology 17 , 32 . In this study, pain persistence was significantly correlated with treatment interruption only in patients using EP. EP treatments were significantly correlated with discontinuation, and this risk was higher in the first nine months of treatment. They are widely used to control symptoms of endometriosis, but various authors question their benefits. Some, for example, cite the lack of response in pain outside the menstrual period and dyspareunia, as well as the suspicion that EPs may induce the progression of endometriotic lesions 32 – 34 . The decrease in the rate of EP interruption over the months may represent patients' adaptation to the side effects of these drugs, so if there is resilience and good guidance on side effects at the beginning of treatment, the chances of good tolerability are higher. It is necessary to highlight that all patients underwent some surgical treatment, which allowed the histological diagnosis to be used as an inclusion criterion for the study. Thus, the benefits acquired by surgery should be considered. The choice of medical therapy for endometriosis is not simple. Several factors must be evaluated, such as main symptoms, reproductive desire, types of lesions found, side effects, comorbidities, and personal preferences of the patient. The importance of the patient's reception by the medical team with proper management of complications must also be emphasized. Conclusion The treatment with combined contraceptives has been associated with a higher risk of discontinuation than treatment with isolated progestins. This risk was significantly higher in the first 9 months of treatment. Among all the described complaints, breakthrough bleeding, weight gain, and persistence of pelvic pain had a direct, significant and independent association with medication discontinuation. Declarations Ethics approval and consent to participate: Informed consent was obtained from all the participants. All methods were carried out in accordance with relevant guidelines and regulations. Consent for publication: Not Applicable. Availability of data and materials: The authors confirm that the data supporting the findings of this study are available within the article. Raw data that support the findings of this study are available from the corresponding author, upon request. Competing interests: No potential conflicts of interest were reported. Funding: This study was funded by the authors. Authors’ contributions: Denise Joffily Pereira da Costa Pinheiro and Ana Maria Gomes Pereira elaborated the structure of the study. Denise Joffily Pereira da Costa Pinheiro wrote the main manuscript text and prepared the figures and tables. Ana Maria Gomes Pereira did the statistical analyzes. All authors reviewed the manuscript. Acknowledgements: The authors would like to express their gratitude to all patients assisted by our group. References Febrasgo (BR). Manual de endometriose 2014/2015. [Internet]. 2015 [cited 2022 jun 29]. Available from: http://professor.pucgoias.edu.br/SiteDocente/admin/arquivosUpload/13162/ma terial/Manual%20Endometriose%202015.pdf National Institute for Health and Care Excellence. Endometriosis: diagnosis and management. [Internet]. 2017 [cited 2022 jun 29]. Available from: https://www.nice.org.uk/guidance/ng73/resources/endometriosis-diagnosis- and-management-pdf-1837632548293 Ministério da Saúde (BR). Protocolos Clínicos e Diretrizes Terapêuticas. Volume I. [Internet]. 2010 [cited 2022 jun 29]. Available from: http://bvsms.saude.gov.br/bvs/publicacoes/protocolos_clinicos_diretrizes_tera peuticas_v1.pdf Chapron C, Marcellin L, Borghese B, Santulli P. Rethinking mechanisms, diagnosis and management of endometriosis. Nature. 2019;15:666-682. Vercellini P, Vigano P, Somigliana E, Fedele L. Endometriosis:pathogenesis and treatment. Nat. Rev. Endocrinol. 2014;10:261-275. Becker CM, Bokor A, Heikinheimo O, Horne A, Janses F, Kiesel L, et al. ESHRE guideline: endometriosis. Hum Rep Open. 2022;1-26. Vercellini P, Buggio L, Frattaruolo MP, Borghi A, Dridi D, Somigliana E. Medical treatment of endometriosis-related pain. Best Pract Res Clin Obstet Gynaecol. 2018;51:68-91. American Society for Reproductive Medicine. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67(5):817-821. Falcone T, Flyckt R. Clinical Management of Endometriosis. Obstet Gynecol. 2018;131(3):557-71. McLeod BS, Retzloff MG. Epidemiology of endometriosis: an assessment of risk factors. Clin Obstet Gynecol. 2010;53(2):389-96. Kondo W, Ribeiro R, Trippia C; Zomer MT. Endometriose profunda infiltrativa: distribuição anatômica e tratamento cirúrgico. Rev Bras Ginecol Obs. 2012;34(6):278-84. Zondervan KT, Phil D, Becker CM, Missmer SA. Endometriosis. N Engl J Med. 2020;382:1244-56. Nácul AP; Spritzer PM. Current aspects on diagnosis and treatment of endometriosis. Rev Bras Ginecol Obstet [Internet]. 2010 [cited 2022 jul15];32(6). Available from: https://doi.org/10.1590/s0100- 72032010000600008 Working group of ESGE, ESHRE and WES, Keckstein J, Becker CM, Canis M, et al. Recommendations for the surgical treatment of endometriosis. Part 2: deep endometriosis. Hum Reprod Open. 2020;12(1):1-25. MIinistério da Saúde (BR). Protocolos clínicos e diretrizes terapêuticas endometriose goserrelina, leuprorrelina, triptorrelina, danazol. [Internet]. 2006 [cited 2022 jun 29]. Available from: http://bvsms.saude.gov.br/bvs/saudelegis/sctie/2006/prt0069_01_11_2006_co mp.html Bulun SE, Yilmaz BD, Sison C, Miyazaki K, Bernardi L, Liu S, Kohlmeier A, Yin P, Milad M, Wei J. Endometriosis. Endocrine Reviews. 2019;40(4):1048- 1079. Barbara G, Buggio L, Facchin F, Vercellini P. Medical Treatment for Endometriosis: Tolerability, Quality of Life and Adherence. Front Glob Womens Health. 2021;2:729601. Kalaitzopoulos DR, Samartzis N, Kolovos GN, Mareti E, Samartzis P, Eberhard M, et al. Treatment of endometriosis: a review with comparison of 8 guidelines. BMC Women’s Health. 2021;21:397. Zorbas KA, Economopoulos KP, Vlahos NF. Continuous versus cyclic oral contraceptives for the treatment of endometriosis: a systematic review. Arch Gynecol Obstet. 2015; 292(1):37–43. Schindler AE. Dienogest in long-term treatment of endometriosis. Int J Womens Health. 2011;3:175–84. Buggio L, Somigliana E, Barbara G, Frattaruolo MP, Vercellini P. Oral and depot progestin therapy for endometriosis: towards a personalized medicine. Expert Opin Pharmacother, 2017, 18(15):1569–1581. https://doi.org/10.1080/14656566.2017.13 81086 PMID: 28914561 Remorgida V, Abbamonte LH, Ragni N, Fulcheri E, Ferrero S. Letrozole and Desogestrel-only contraceptive pill for the treatment of stage IV endometriosis. Aust N Z J Obstet Gynaecol, 2007, 47(3):222–225. https://doi.org/10.1111/j.1479-828X.2007. 00722.x PMID: 17550490 Vercellini P, Aimi G, Panazza S, Giorgi OD, Pesole A, Crosignani PG. A levonorgestrel-releasing intrauterine system for the treatment of dysmenorrhea associated with endometriosis: a pilot study. Fertil Steril. 1999;72(3): 505–508. Fedele L, Bianchi S, Zanconato G, Portuese A, Raffaelli R. Use of a levonorgestrel-releasing intrauterine device in the treatment of rectovaginal endometriosis. Fertil Steril. 2001;75(3):485–8. Petta CA, Ferriani RA, Abrao MS, Hassan D, Silva JCR, Podgaec S, et al. Randomized clinical trial of a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the treatment of chronic pelvic pain in women with endometriosis. Hum Reprod. 2005;20(7):1993–8. OpenEpi online version. [Internet]. 2013 [cited 2022 jul15] Available from: http://www.openepi.com/DiagnosticTest/DiagnosticTest.htm Santos TMV, Pereira AMG, Lopes RGC, Depes DB. Tempo transcorrido entre o início dos sintomas e o diagnóstico de endometriose. Einstein. 2012;10(1):39-43. Arruda MS, Petta CA, Abrão MS, Benetti-Pinto CL. Time elapsed from onset of symptoms to diagnosis of endometriosis in a cohort study of Brazilian women. Hum Reprod. 2003;18(4):756-9. Soliman AM, Fuldeore M, Snabes MC. Factors associated with time to endometriosis diagnosis in the United States. J Womens Health. 2017;26(7):788-97. Vercellini P. Endometriosis: What a pain it is. Semin Reprod Endocrinol.1997;15(3):251-61. Vercellini P, Buggio L, Berlanda N, Barbara G, Somigliana E, Bosari S. Estrogen-progestins and progestins for the management of endometriosis. Fertil Steril. 2016;106(7):1552-71. Donnez J, Dolmans MM. Endometriosis and medical therapy: from progestogens to progesterone resistance to GnRH antagonists: a review. J Clin Med. 2021;10(5):1085. Casper RF. Progestin-only pills may be a better first-line treatment for endometriosis than combined estrogen-progestin contraceptive pills. Fertil Steril. 2017;107(3):533-36. Chapron C, Souza C, Borghese B, Lafay-Pillet MC, Santulli P, Bijaoui G, et al. Oral contraceptives and endometriosis: the past use of oral contraceptives for treating severe primary dysmenorrhea is associated with endometriosis, especially deep infiltrating endometriosis. Hum Reprod. 2011;26(8):2028–35. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 23 Sep, 2023 Read the published version in BMC Women's Health → Version 1 posted Editorial decision: Major revision 07 Aug, 2023 Reviews received at journal 06 Aug, 2023 Reviewers agreed at journal 15 Jul, 2023 Reviews received at journal 15 May, 2023 Reviewers agreed at journal 30 Apr, 2023 Reviewers invited by journal 07 Apr, 2023 Editor assigned by journal 02 Apr, 2023 Editor invited by journal 29 Mar, 2023 Submission checks completed at journal 29 Mar, 2023 First submitted to journal 07 Mar, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2667012","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":187463565,"identity":"f1487cc9-a1be-4880-abb4-fa3bbcf7df5d","order_by":0,"name":"Denise Joffily Pereira da Costa Pinheiro","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+klEQVRIie3QsYrDIACAYb2AWWw6d+m9QqCP0yXZzz1DWgwHuaW3dwi9V2iXrqcIZpF2LXRobs9ym7ccZ7zrmJqxcP6IiPhhDAA+3z3G7EAgfOYFA5nZCQI6jGCZUgZUR6Cb2LBMAINlt3SQqH7lXGfRFKOAitFmMR+/GKKzfS+ZqEMisEIzjKAh+5qsBaRwpc69JD49xQKWKH1/LDoiCTUkgOUNcmlj/vWN0pW9pZLkzUlOOGYjeiU0J1sXmSjzYVj+voVXkpGdIfzWW6JazT51Ls0fCz+aNl+SzVHwRmf95C9p5wcMhF0w13lTbmeowXLAYZ/P5/tv/QDON2SyrFtM0gAAAABJRU5ErkJggg==","orcid":"","institution":"Hospital do Servido Publico Estadual - Francisco Morato Oliveira (HSPE-FMO)","correspondingAuthor":true,"prefix":"","firstName":"Denise","middleName":"Joffily Pereira da Costa","lastName":"Pinheiro","suffix":""},{"id":187463567,"identity":"48693ed0-6f2c-4b03-96e6-b33106327759","order_by":1,"name":"Ana Maria Gomes Pereira","email":"","orcid":"","institution":"Hospital do Servido Publico Estadual - Francisco Morato Oliveira (HSPE-FMO)","correspondingAuthor":false,"prefix":"","firstName":"Ana","middleName":"Maria Gomes","lastName":"Pereira","suffix":""},{"id":187463571,"identity":"31ba01c1-f233-4fca-ad2c-45e20e4e304b","order_by":2,"name":"Marcelo Antonini","email":"","orcid":"","institution":"Hospital do Servido Publico Estadual - Francisco Morato Oliveira (HSPE-FMO)","correspondingAuthor":false,"prefix":"","firstName":"Marcelo","middleName":"","lastName":"Antonini","suffix":""},{"id":187463575,"identity":"a686aa64-19a9-4b88-a972-4ad81c689060","order_by":3,"name":"Isabella Maria Albuquerque Salgado","email":"","orcid":"","institution":"Hospital do Servido Publico Estadual - Francisco Morato Oliveira (HSPE-FMO)","correspondingAuthor":false,"prefix":"","firstName":"Isabella","middleName":"Maria Albuquerque","lastName":"Salgado","suffix":""},{"id":187463579,"identity":"b3245fed-d575-4754-b844-a5b71943a073","order_by":4,"name":"Alexandre Torchio Dias","email":"","orcid":"","institution":"CEDEP – Instituto de Assistência Médica ao Servidor Público Estadual (IAMSPE)","correspondingAuthor":false,"prefix":"","firstName":"Alexandre","middleName":"Torchio","lastName":"Dias","suffix":""},{"id":187463580,"identity":"e0d9d535-ae10-470f-a944-bc09f3490f7b","order_by":5,"name":"Reginaldo Guedes Coelho Lopes","email":"","orcid":"","institution":"Hospital do Servido Publico Estadual - Francisco Morato Oliveira (HSPE-FMO)","correspondingAuthor":false,"prefix":"","firstName":"Reginaldo","middleName":"Guedes Coelho","lastName":"Lopes","suffix":""}],"badges":[],"createdAt":"2023-03-07 21:14:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2667012/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2667012/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12905-023-02647-y","type":"published","date":"2023-09-23T15:00:38+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":35067771,"identity":"368a60a9-4420-4e16-9475-fe46846fec71","added_by":"auto","created_at":"2023-03-30 22:44:33","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":18181,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of patients attended by the Endometriosis sector of the State Public Servant Hospital in São Paulo.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-2667012/v1/a389db8a5bd5ffccdf6494bd.png"},{"id":35067447,"identity":"827a11a2-adf7-4287-8777-a372cc793f63","added_by":"auto","created_at":"2023-03-30 22:36:33","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":33889,"visible":true,"origin":"","legend":"\u003cp\u003eTime elapsed between onset of symptoms and surgical diagnosis.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-2667012/v1/1af69f1a3d06ca22242c58bd.png"},{"id":35067449,"identity":"7fc1a932-3f5e-4dbf-b191-43ef20f72d85","added_by":"auto","created_at":"2023-03-30 22:36:33","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":32494,"visible":true,"origin":"","legend":"\u003cp\u003eTime of use of the medication proposed as the initial treatment.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-2667012/v1/0c451679fddbd78a26a01efc.png"},{"id":35067446,"identity":"301c82c8-a566-485a-87f9-721f3f893fd8","added_by":"auto","created_at":"2023-03-30 22:36:33","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":26498,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of medication treatment and evolution.\u003c/p\u003e\n\u003cp\u003eEP Estrogen-progestins, P progestins, A GnRH analogs\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-2667012/v1/293f70dff9c54b577b953269.png"},{"id":43640317,"identity":"7e4429eb-e6f4-4b43-ab28-98007a5be3bf","added_by":"auto","created_at":"2023-09-25 15:05:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":687940,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2667012/v1/1d398cfb-ea6b-43e0-bd58-4c8d551de742.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Tolerability of endometriosis medical treatment: a comparison between combined hormonal contraceptives and progestins","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEndometriosis is a chronic inflammatory estrogen-dependent gynecological disease characterized by the development and growth of functional endometrium-like tissue outside the uterine cavity\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. It predominantly affects the ovaries but can also affect other organs such as the fallopian tubes, pelvic ligaments, \u003cspan refid=\"Sec5\" class=\"InternalRef\"\u003eappendix\u003c/span\u003e, bladder, and intestines\u003csup\u003e\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe most common symptoms are dysmenorrhea, pelvic pain outside the menstrual period, dyspareunia, infertility, urinary and evacuation symptoms. However, its clinical presentation can be non-specific and with symptoms disproportionate to the extent of the disease, making diagnosis difficult\u003csup\u003e\u003cspan additionalcitationids=\"CR7 CR8 CR9\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eEndometriosis significantly impacts women's quality of life, compromising their social and emotional relationships, work, and study performance. It is an important public health issue, affecting 6 to 10% of women of reproductive age, with a peak incidence between the ages of 25 and 35 years\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe treatment of endometriosis includes surgery, medication therapy, and assisted reproductive techniques. As a chronic disease, patients should be monitored for many years and receive individualized treatment according to their clinical status and reproductive desire at each stage of life. The goal is to remove endometriotic foci surgically or suppress them with clinical treatment. However, the best approach has not been defined yet\u003csup\u003e\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe medical treatment aims to induce a hypoestrogenic state of chronic anovulation, creating an inadequate environment for the growth and maintenance of endometriosis implants\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. The medical treatment is not curative, as it cannot eliminate the endometriotic foci, only making them temporarily inactive during medication use\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAmong the therapeutic options, we have combined hormonal contraceptives containing estrogens and progestins (EP), isolated progestins (P), antiprogestins, GnRH agonists, GnRH antagonists, aromatase inhibitors, and medications that do not act as hormonal suppressants, such as analgesics and non-steroidal anti-inflammatory drugs\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eConsidering the chronic use of these medications, it is important to evaluate not only their efficacy but also their tolerability, side effects, cost, and each patient's preferences\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. The tolerability of treatment consists of the patient's ability to tolerate the side effects and maintain the use of the medication. It can be evaluated through the rates of treatment interruption or follow-up losses in clinical studies\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIt is recommended to start with low-cost drugs, such as combined oral contraceptives and some progestins, and then move on to high-cost drugs, such as GnRH agonists, in cases of low adherence, tolerability, or ineffectiveness\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAlthough widely prescribed, combined hormonal contraceptives have no scientific basis to prove the superiority of this group of medications compared to other classes, and does not appear to be any advantage of any specific drug within this group\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Continuous administration of combined contraceptives has been more favorable in controlling pain than cyclical administration. It is possible to perform a planned interruption only to control spotting, which is bleeding that occurs outside of the menstrual period\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Regarding ethinylestradiol dosage, low-dose options with 20 mcg are safer, with a lower risk of thromboembolic events\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAccording to some authors, progestins have fewer side effects than combined contraceptives and can be prescribed in various routes of administration, oral, injectable, implants, and intrauterine devices\u003csup\u003e9,20\u0026minus;25\u003c/sup\u003e. Desogestrel and dienogest are 19-nortestosterone-derived progestins widely studied for the treatment of endometriosis and have been shown effective in controlling symptoms\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSymptoms can be controlled by various drugs, many of them with great pain control results, the limiting factors are the side effects and tolerability related to these medications. Adequate monitoring and control of unwanted effects are essential for achieving therapeutic success. Thus, studies that compare drug options, considering not only the efficacy but also the quality of life of patients, are necessary to guide conduct.\u003c/p\u003e\n\u003ch3\u003eObjectives\u003c/h3\u003e\n\u003cp\u003eThis study aims to compare the discontinuation rates of medical treatments for endometriosis with combined hormonal contraceptives and isolated progestins. The secondary objective is to evaluate the main adverse effects related to the discontinuation of these medications.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eA retrospective study that evaluated the rate of medication interruption by patients attended in the endometriosis sector of the State Public Servant Hospital in S\u0026atilde;o Paulo.\u003c/p\u003e \u003cp\u003eThe data was collected through forms filed in the specialized outpatient clinic. Patients attended from August 1999 to September 2020 were evaluated.\u003c/p\u003e \u003cp\u003eTo be included in the study, a histological confirmation of endometriosis and a medical treatment prescription was necessary. Patients with incomplete data for the study, those who were already in clinical or surgical postmenopause at the first consultation, hysterectomized patients and finally, those patients who did not have a minimum follow-up time of 6 months in the presence of medical treatment were excluded.\u003c/p\u003e \u003cp\u003eEpidemiological data were collected to trace the profile of attended patients.\u003c/p\u003e \u003cp\u003eThe time between the onset of symptoms and the surgery date was evaluated. The symptoms questioned were dysmenorrhea, dyspareunia, cyclic pain, pain while evacuating, pericicatrical pain, infertility, urinary and intestinal symptoms.\u003c/p\u003e \u003cp\u003eThe surgical findings were raised, researching where endometriotic lesions were found. The surgical procedures performed and the staging of endometriosis were also researched. The classification of endometriosis from the American Society for Reproductive Medicine (ASRM) was used as a reference\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe prescribed medications for clinical treatment were chosen based on reliable guidelines such as ESHRE\u0026rsquo;s, on the opinion of the attending physician and on the patient\u0026rsquo;s preferences\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. These treatments were verified for the type of hormone and dose. During the entire follow-up, patients were questioned about the symptoms and side effects presented during treatment. The use time of each medication was recorded, and once the patient opted for discontinuation, the reason for discontinuation was also recorded. A new medication could be prescribed, containing the same hormone with a different dosage or a medication from a different class.\u003c/p\u003e \u003cp\u003e An informed consent form was applied before data collection. This study was approved by Research Ethics Committee of State Public Servant Hospital and is registered in Plataforma Brasil under CAAE number 36271213.8.0000.5463.\u003c/p\u003e \u003cp\u003eStatistical analyzes were performed for two distinct groups, isolated progestins (P) and combined contraceptives (EP). Frequencies were calculated using the information available for each data point.\u003c/p\u003e \u003cp\u003eThe data obtained were grouped in an Excel spreadsheet for Windows\u0026reg; and were analyzed using the statistical programs Epi Info7\u0026reg; an Open-Epi, online version\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. Continuous variables were tested for their distribution and are presented in means and standard deviation or medians and quartiles, depending on the normality of this distribution. Categorical variables are presented in percentages, according to the data available for analysis.\u003c/p\u003e \u003cp\u003eThe variables relating to adverse events and complaints reported during clinical treatment were correlated with the outcome of treatment interruption, and multiple analysis of logistic regression was conducted using the STATA 12.0\u0026reg; program, grouping the adverse events that presented potential statistical significance in the univariate analysis (value of p\u0026thinsp;\u0026lt;\u0026thinsp;0.25 was used to select variables for multiple final analysis), except those that did not have enough outcome events to be included in the adjusted modeling.\u003c/p\u003e \u003cp\u003eA p-value\u0026thinsp;\u0026lt;\u0026thinsp;0,05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eAs reported in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, we enrolled 392 patients in the study, and after applying exclusion criteria, 330 patients remained for analysis\u003c/p\u003e\n\u003cp\u003eThe average age of patients at the time of the first consultation was 37.57 years (+/- 6.27), ranging from 17 to 53 years. The average age of symptom onset was 31.07 years (+/- 8.4), ranging from 8 to 51 years.\u003c/p\u003e\n\u003cp\u003eThe average age of menarche was 12.46 years (+/- 1.73), ranging from 8 to 17 years. Out of the total, 138 patients (42.72%) had no children at the time of the first consultation and 40 patients (12.39%) had had one or more abortions.\u003c/p\u003e\n\u003cp\u003eHormonal contraceptive methods were used by 145 patients (46.17%), 36 (11.46%) used permanent methods, and 96 (30.57%) used only condoms or no method. Three patients were using GnRH analogs at the time of the first consultation. Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e describes the most common conditions; arterial hypertension was the most frequent.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" id=\"Tab1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePersonal medical history reported by patients at the first visit.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eComorbidities\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFrequency\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePercentage\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCancer\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.12%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCardiopathies\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.03%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiabetes Mellitus\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.85%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eArterial Hypertension\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13.03%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eThyroidopathies\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.15%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eGynecological Diseases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.06%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePsychiatric Diseases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eOf the total, 18 patients (5.45%) were asymptomatic at the time of the first consultation and 3 (0.91%) received the diagnosis in surgeries indicated by other hypotheses, making endometriosis a surgical finding. Twenty-five patients (7.57%) did not have data for calculating the time of symptoms. Thus, 284 patients remained, with whom it was possible to calculate the time between the onset of symptoms and the diagnosis. The median time between symptoms and surgical diagnosis of endometriosis was 31.1 (14.13\u0026ndash;63.53) months, ranging from 1.03 to 426.13 months, data illustrated in Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eTable \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e illustrates the symptoms reported by the patients before starting prescribed treatment. In Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e, it is possible to evaluate the main sites of endometriotic lesions described in surgical reports.\u003c/p\u003e\n\u003ctable border=\"1\" id=\"Tab2\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eSymptoms reported by patients at the first appointment.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" style=\"width: 41.0294%;\"\u003e\n \u003cp\u003eSymptoms\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" style=\"width: 29.2647%;\"\u003e\n \u003cp\u003eFrequency\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" style=\"width: 18.0882%;\"\u003e\n \u003cp\u003eTotal Available\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" style=\"width: 11.6176%;\"\u003e\n \u003cp\u003ePercentage\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 41.0294%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDysmenorrhea\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 29.2647%;\"\u003e\n \u003cp\u003e266\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 18.0882%;\"\u003e\n \u003cp\u003e329\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 11.6176%;\"\u003e\n \u003cp\u003e80.85%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 41.0294%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDyspareunia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 29.2647%;\"\u003e\n \u003cp\u003e144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 18.0882%;\"\u003e\n \u003cp\u003e327\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 11.6176%;\"\u003e\n \u003cp\u003e44.04%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 41.0294%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAcyclic Pain\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 29.2647%;\"\u003e\n \u003cp\u003e144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 18.0882%;\"\u003e\n \u003cp\u003e329\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 11.6176%;\"\u003e\n \u003cp\u003e43.77%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 41.0294%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePainful Defecation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 29.2647%;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 18.0882%;\"\u003e\n \u003cp\u003e329\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 11.6176%;\"\u003e\n \u003cp\u003e3.95%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 41.0294%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePericicatricial Pain\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 29.2647%;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 18.0882%;\"\u003e\n \u003cp\u003e329\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 11.6176%;\"\u003e\n \u003cp\u003e4.26%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 41.0294%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eInfertility\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 29.2647%;\"\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 18.0882%;\"\u003e\n \u003cp\u003e326\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 11.6176%;\"\u003e\n \u003cp\u003e18.71%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 41.0294%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHematuria/Urinary Symptoms\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 29.2647%;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 18.0882%;\"\u003e\n \u003cp\u003e328\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 11.6176%;\"\u003e\n \u003cp\u003e2.44%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 41.0294%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eConstipation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 29.2647%;\"\u003e\n \u003cp\u003e102\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 18.0882%;\"\u003e\n \u003cp\u003e320\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 11.6176%;\"\u003e\n \u003cp\u003e31.88%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 41.0294%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntestinal Bleeding\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 29.2647%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 18.0882%;\"\u003e\n \u003cp\u003e328\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 11.6176%;\"\u003e\n \u003cp\u003e0.61%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 41.0294%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTenesmus\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 29.2647%;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 18.0882%;\"\u003e\n \u003cp\u003e329\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 11.6176%;\"\u003e\n \u003cp\u003e1.52%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003ePercentages are calculated based on available data.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003eTable 3. Location of endometriotic lesions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cimg 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4+qKROdA6lq2l05n6ybp1YycXrZvPFd7gIlk+UxJ+b0pn0f9FcAczVfHoh1jNo2OyzK541LHgvrbPJRyx4fm649Hvyw/bY7G89vmy5FUXfnQpPzQ3Wq/nUpad12B1baWSa/QVo0LoJkmx2wTbcq8dJn6v0ovZUab9RFfBrato+TKbv1vNL762fS2Hukdq7T+pPn6aTV/W3bd+rbd/jqz9KczEwAABo6uYprOSXNCr6YOCv1Onn7iQToVhCsatwGAYaH3pOwdq6k4J/BoHwAAA0ovWlsQJT//+c9jFwDMPNYohJJ+S8q33KeGhHxDFVPxUzPckQIADKxhvSPlt9vMnj27+Pbbb+N/ADDzKHg6f/58/K+cysMvv/wytNg3mbgjBQDAgFmcedlaDXPMFL45YkvWzHE/0ONDtl47duyIfUdM5Dpr+l7np/Wy6bS+wEzw0ksvxa5qKg8nO4gSAikAAAaMfs/KKKhSi6AT9btW002teuXe83rzzTdjF4BhpZZKdUdq/fr1V1xQWrBgQeh/7NixKSsPCaQAAANLT6dbGqaGJnS11bb75MmToXIxUxw5ciT7o5oKrpr8HAWAmU3NmqsMVNnnzwHnzp0L/dXU+VQhkAIAAH3jgw8+iF3dv0Oj4EpBVj84ePDgaOVtGFuKBDCCQAoAAPQF3XHSD3Kahx9+uCuYeu2112JXN72Abu8DlTX/PmfOnNJx9O6RHgXy42ieelfLtwpmqt6RqqLt0/h6NNOmV9L8mjZbr/H89Frvs2fPxqHtpOuibjWnz50/oKHLAAAAfUA/vK6qiZJ+MFP0o+vWTyn34+b+R4n145opPw+br9EPcdqwXNL4+uFTr+pHP/20/gdV9SOi+rFUPzxN/sdKRdP74VXTpz8oqvWyYek+qVuX3DYDuBJ3pAAAQF949dVXY1cx+rK43v9SU8bmvffei11jHn300dhVhN+RSe8iffjhh7FrbL6iOy+66yRahl5S79SNik4QMbpMPVKo36cZr7179xanTp0K3XohvhPMhGWp2+zatSt7B8zY9Dlld89yHnroocp5aZt/8YtfcGcKqEEgBQAApp2CAF+5X716dezqDn5eeeWV2DVGL5/7Frz8u1QKBhSgmMcffzx2jQRl1rCFlmEvqS9cuLBrmU0DlCrPP/987CqKp59+erRpZnV7X3/9dey6koK7ffv2hQBMgdjmzZvjkJHgR8FaHT0G6H+0dPfu3aNBneZtAaRaRuuXd9KAfkUgBQAApp2vtKsy71sifPDBB2PXSAU/93tKv/nNb2JX950tP181j6wgySioUgChNNm/w6UfS7ZlKfDrhdbRAjwFYlu3bi1WrlwZ/pfTp0/HrnI+iNK02gcW1Gne/g6Zb/gDwJUIpAAAwLT7r//6r9jVfQdKdKdIQZDJ/abU8uXLY9fII3B2F8kHA4899ljsupKCMzW+oGWr0Ql/F2siab3UYIQadVDjDn676tx6662xa8ydd94Zu4rixIkTsavcRx99FLtGgipraMLStm3b4tCi+P7772MXgBwCKQAAMK30uJnuNBkFMWkF3w9XIJK+v6O7Kv5uiu5EaRzfCuCaNWti1xgFTwqcli1bVmzatCmMb4/7TSRto1rnU+C0bt26ELBUvaeUU3cna6LXu0lgBgwzAikAADCt3nnnndjVjAKG3Ps7/hFAPd7nx9FjbGkgoiBKwZMFIApyFIzpXSEflI2XAro77rjjisfqtm/fHhq4aKqumfM2d7dE71jZ44a5pMcRAZQjkAIAANPK3zVqKvebUv4RQN3tefHFF0O3PPLII7FrjG+4Qr9Xde7cudH3kK677ro4ZPwU0Pm7RWoVUD/qqx/ztQYumvCBmPGP6um3r+rccsstsau3/Q5gDIEUAACYNgcOHOh6bG///v3ZuyNKvpU6BRW51vT8e1D26Jwar/DvUBm/XP34r/fuu+/GrvG7cOFC7CpC64K+wQttf1O6e2ZNsesul+6o+eDq3nvvjV3l7r777tg1sv2+2XS9J+Z/lHgimn0HZjICKQAAMG38bzylrfWl7r///tg1IvebUrn3oHSHyVqm8/yjcH/4wx9CcGIBStv3l6pce+21sWskuNM7XqLARctt44knnghBzrx580JgZbTvctue0h0w39Kf3kfTftA89Z6Y3TlrOj9gmBFIAQCAaWNBhaxYsSJ25elOjg9+yn5TygcK4t+d8l566aXYNRLgKDixAMUvJ/dIXRsK5PzvXKmxCQtctFy/rOPHj8euK/l5eAp6jh49mg0Wc954443SeUnb+QHDikAKAABMCz3W5t8d+vnPfx67yv32t7+NXeW/KeXfh1KQUvYeku5+6VFCH1SoW41AfPLJJ10Bjg/4eqF3otSAhYIU0afey1JjE88991zoJ7ng0GgeWjdbL81D81Qw5h8XrKMAyeblt13z7WV+wLCadVkPHQMAAAAAGuOOFAAAAAC0RCAFAAAAAC0RSAEAAABASwRSAAAAANASgRQAAAAAtEQgBQAAAAAtEUgBAAAAQEsEUgAAAADQEoEUAAAAALREIAUAAAAALRFIAQAAAEBLBFIAAAAA0BKBFAAAAAC0RCAFAAAAAC0RSAEAAABASwRSAAAAANASgRQAAAAAtEQgBQAAAAAtzbrcMWvWrPgvAAAAAKBOCKRiNwAAAACgAR7tAwAAAICWCKQAAAAAoCUCKQAAAABoiUAKAAAAAFoikAIAAACAlgikMOE+/vjjYsOGDcX1119fqGl9S3fddVexZcuW4quvvopj9r8dO3Z0rT+A6ffWW2+F49GOzTlz5hQPPPBAKHuasunb+Oabb8KyNF2bZWFw6DtOz191eUvT6FyxZMmS0Wk0veZTdb7LLUvzUP7GcMnlH/VTHsnx4+ZSL/WVAwcOXFGu1uXhlNWZypav7dHxZMtQd9X8tZ3aF31NzZ8DE+HixYuXV65cqeb0a9P27dvjVP1N62nrrG0DML3Wr18/ekwuXrw4HJcLFiwY7dekbPHzaGPt2rWj0x07diz2xUxx5syZy7Nnzw7frz6Vt5TH7Dvft29fHHOMznt+HE2j5Oezf//+OPaYumUpj2LmK8s/9r+GaZyUDS9LmkcbuXLV50/l1zoap275tq2bN28OSfNWym2jjjeNmzvu+gmBFCZEWhg0SYNwoiCQAvqHHY868aaBzO7du0eP1bIgR+WUD4aUmrKTuiUCqZnHKrA6N/mKnf/u0+/dptH57/z587HvSF6zymlaUVS3Bf/psjT/smVh5rHyKM0/6rY8kl4csjyiaSaClZ1puap8aetXV//RuL4OmBtfFxQ0TAGUsWNL65DS9k/UNk4mAilMiLRyosyvg8ZOECoUVBjoQPXj5a7UAUCOVSzKrlBaxVXlUUrTpOWPUhMqvzStv/NFJXdmsavpadBjLG/5SqDyheUHXwn2LM/4iqJVXMsqp1pGuizMPHV5zgKPNJiwC0oTlT+sXMyVaVovDVPKraOxPGv5PZe3bb39cmwfpOPnxu1XvCOFcTt79mzx9ttvx/+KonPQFwcPHixWrVpVzJ07N/SbP39+sXHjxuLo0aNF56AN/eTJJ5+MXUXXc+Jlz4jb+wm5cdL3JpT0fG3Zc8Z+PD0bnD63a8+9W7+yZ37TZ5vVrXfByp5t1rP2mr/fFnsWWfsSQJ6VHcuXLw+fqdWrV4fP77//PnwaHaPr1q0rvvvuu6ITZBWdCkoc0oym0bR//etfYx/MNF988UU4d61YsWL0vOVdd9114fP06dPhU3744YeiU3EM0+kcl6O8I5cuXQqf8uqrr4ZPf/7ztm7dqgg/fGLmeuedd8JnJ0jP5jnVoZQPTp48GfuM+PTTT8Pnv//7v4fP8VDdR2Wb8vDtt98e+47RemkdlHLrKJrHtm3bQl5/7LHHYt9mFi5cGLvGqO70/PPPF53gKrtOfaezc4BxsSsRlsquzBm70mDJnr3186m6LaykKyieXS0sS7qik15N8cP9lWb7X/y6puuk+Wm+fjqftI62bSZ9PCiXuEsH9MaO19zVTZURdnVTn3a81bF56lNsukG4UoqJozyl7z33CFIVm87yj1gewnCzvNG2LLH6iu68+zqI+iufVd05SqXlW1taluo6Suq2+aVlsNgwv712R0rbYqwuWFeX7BccyRg3KwyUdFDX8Y9DKNkBnPZPDyIfLKnb+EqRlm/TpUFL+jiQH5YmG9cOfKW0YPDbXZZUsPlCTYWN+uvTChMN99tmBRKA5nTMWAWjrrLry4wqNp4v12w6XxnAzKULW1bWKx+0KZutkqhkF9XSPKVzjbptPC2Li2nDwb5z5SnlCwUT1k95IhfcpPUklXnKMz4PtcmnlreV5zRv1UWsnqJ56/+qefnppSqQ0jga5h9JtHqaldm2fb6O1+8IpDBudtCVHTw5Nr6SLyx8YeArQzqQ/TT+To8vfNJgySpWSmmhZP0t5SpfZYGUP0HatFbYaB38PrF18pW3NMCS3DQAmrGLEU0uRPhjsYzmoeNU8/MXdWw6AqmZTWW6fddKbSqnonHtfObPHZb31M/yrFWGq85XmHnsu7ZgQmWN8oGvB/m8I6p7aLjGTcsgG5abrozG0/jK71YHUT/rr6R86ctAY8eID4yqAimx9dM0Slqmrw+pPpeWuf2OQArjZgdb1cGT8tP4E4YVKEo64Izvr4OuCX8iU6oKpPyyvLJAqqy/sVvTSnbLOg2+bJi2bZAKDaDfWIVUqUmA0ySQsgs06UWNNsvB4FIZr7Jdyb5znSf8Rbwy/tyjSqEPwHzeU0ov4PkAjjw2s/l8kN750XdvgU1ad6lid3SUmtzZTPO3r4uo2/JxWs+x+oyG+/W2ulGuXiQa15fXKmdtmXZs2Pam42qeTY6/qUYghXGzg90yehM2vpIvJHTg+GF2gFmlJh3f07QqODTcFw5l01UNM+pv4/hty82/LPnp/BXHNGmYlucLJQDV/Ik2DXrK+Mpsjl24sYsgnk1HJXd4+Aqlv3qeo2E+iEorfj7vlZ13LE/n8h9mDssHZfUmK4eUj9qw+klZ/vJs3DTgN8r7tp6Wl30eT/O31ZnKtqmKpvHrYeum40Hz1TAlqxf2C1rtw7jdeuutsasozp07F7vKVbVMp1ZhOgdN/K8ojhw5Elpw8a0CrlmzJnaN0HC1eDdv3rzinnvuKTZt2lQcOnQoDp1+J06ciF1FaPWrUwDF/7p1Coew7j/96U9pvQ+ooeNeLWnu2rUrtObXqaCG1jDHS7+yr/JE8/zLX/4S+2KYqUU+tUQrKqd1XspRub106dLi1KlToZzXZ65VMtOpKMaubg8++GD49Oc9zFz33ntv7Opm5Zla1VNrv03dcsst4dNa92uirLVK5X3Lp1av+vOf/xzydie4qczfbajlP81/586dYT10LOl/1QfVT60+v/7662Ff7N27N07VHwikMG520IpOMnUHfBrk3HbbbbFrhJ1ERM3E+pOWDui0mdmHHnooVKaMTmCbN28OTRyXBS0TScu6PHJ3N5u+/fbbOOZIU59qylTrpgJClbWUCoo//elP8T8AKauwqixZsGBB+FmFiWom97333gvHoJIuzthPFFgyy5YtC/+raXXMfKrcWYXywoUL4dPTz2/ccccd4Ryo8RR45ZpEv+qqq2JXvulnDA87/994443hsyldRNIFnzIqu0RlY50f//jH4XPRokXhswk1dS668JuWj+onKputXxP6KQCtrwWPVk/0x4iagxf/EwT9gEAK43b//ffHrhFPPfVUONBzVAHS7wMYHThpBUj/WwGgqx4vvvhi6JZHHnkkdo1QYeIDs927d4dARb+/4X/HaqL54LGXq4ZaN11lUZB15syZsN6+0ONKJJCnMsQqrLpQ8sknn0xohfTaa68NFeGyZLRs/a/xMfj023/6LcNeAmMFUfY7ZbpApiCq7NyjvGoV6LqLjrkLbZg5dBdIjh8/Hj6rWACuQEMXeF544YXwf4797lSTskllqXz00Ufhs8rVV18dPtMy0SerxyjvWr86e/bsCeX5a6+9FvuMaRtkTovLwATw7zApdQ6m8HyvPevaOUhGn3H145W9DGnP2fqkadNneP3z5kp+uLr9MM3Tqxpm/Hp0CoTY98rl6hlebaMN89tpLxP7Big6lbDQz/PL0v4D0E3HmB1bOubS8qApf/y2ZdNpHpg5rJGHsrJX74LYd+/fC9E5zPpbWV9HeVfjl70DZcP1iZnL3oFSnsuVZX64sXyaqw+JL9usTlJF49j46ftO4oc3mZ/VY3x9qYq2QduSjm/bmR5TbeY9VQikMCF0MCg4sAOuSao6SfiDt2r8dDwbR/3T4G4iAynR/34eueQLO62TD7A0bz/M77+y9QGGmR1z4z2REkghZRU6fbc6j1jZLKpgWvns856fpk2Z7c9b6XRWgVTSeJjZFCTpu1Z9xec5lS+WtxRQGZ/nqqZpkx+V3zWN8rgPpny9pKq+5mm5Gr9pGW3jp+WpXbjwFxvsooUuSvcTAilMGB3QTYILpSYHeTqvsoqLv9OTJiuklNID249Xtj52kOem1/ZWBY8q0NIrPL6gK0tNCyBgmOjYyR0vuVR3DPl5tWXTlZVHGFwqr6181qfykS/j1e0rrv78UJfSc4wqx+my/PnKV54xcynPpfUUn+dyAUxdPi0Lemx4WnaldTfNK/3f5/sqdkxo+jp2QaFsfW0dNFzz1bYq9dsFBgIpTDgdpMr4/sC2A0tBT9ODwG5rK/lb2zk6yNLCSNPbgWrJL9v3T09yxgoFpVzBoMJF4/ht1Xpo+8u2U/21H3L7h5MnkOePxbqUO1Y9AimUUfms8jt3Pkmpv41Tl3LnGFuWrxTrCjx5a7hYPaJJnjNt8qmx8cryl6b19RJ1a72aBlFi5XRdGSxaf41bVlfSclVXsuNDx0Z6cbofzNKfzgoCAAAAABqi1T4AAAAAaIlACgAAAABaIpACAAAAgJYIpAAAAACgJQIpAAAAAGiJQAoAAAAAWiKQAgAAAICWCKQAAAAAoCUCKQAAAABoiUAKAAAAAFoikAIAAACAlgikAAAAAKAlAikAAAAAaIlACgAAAABaIpACAAAAgJYIpAAAAACgJQIpAAAAAGiJQAoAAAAAWiKQAgAAAICWCKQAAAAAoCUCKQAAAABoiUAKAAAAAFoikAIAAACAlgikErNmzapN119/ffHAAw8UBw4ciFNNr2+++abYsWNH8fHHH8c+w0Hb67+X6aT9b+tx1113xb7N6Pvbs2dPmM5vj/LZhg0b+u57Hdb8hsGm/Kpye86cOeH40qeOr6+++iqOAYyUb8oXKn+tLFa+qSrvrExcsmTJFeV3Vf7KLUvzeOutt+IYGHbKC75uoHKrLj/m2PRNUk4uf6uf8nCO1tvytT5VxymjurTGG9h8fxldtEvapM2bN8cpp8f+/fsvL1iwIKzLsWPHYt/hoO3138V02r59++h6rFy5Mvatd+bMmcuzZ8/u2o5cWr9+fZxieg1zfsPg2rdv3+ixpONNx6jlY/2v4YAvjy2fLF68eDTv5PLJxYsXu8bRNEp+Pio3U3XL6pcyH9NHecDyg/KGL7eUVO9oyqapS8qLXln+tv81TON4yu82TOto45etr7ZJaVARSCUsc7RJ01mh7Jf1mA6DHkip8PGFYl1qU2hOFr8+BFIYBL6cUMXEn/QtwFLl4fz587EvhpVV+MryiVJa7tk0qjT6PKTprSKs/OXn58v+dFk+v1LGDi+rUyjvpPlg9+7dE5pHfFCfzm/t2rWhf5q/1W15OK2bWODl87XGTYM0sWMrd7FhUBBIJfSFWsplUGUMX2lWUkE4Xfx6UOhOn14CKX9yVtI8fEGlgsUKJKVcITTV/PqS3zAIrCJQdlzasTud5TimnyqTygdp0GMsKPJPoai8Vj8lX3Z7VtlU5ddYRbgsT2oZ6bIwXCzf5O6CiuVHlW/jobxu9Yw0IKo7JvydJ0/90rxt5bCvN2iemnfTOlO/4h2plubOnVts3Lix6GTy2KfIPgOde/ZZz7lWPScqZ8+eDdPZc/xKei41fRbVnpn1li1bNrqcVJvnbP06lz2z6tcvHSddllJuG1IabsvW/LUfNL7623z8tmndrb+S56dRt74jv19t/mXPr9v4fl9U7bNeXLhwIXYVRacgCvlq/vz5sU9RrFq1qvjjH/8Y/yuK7777LuSPlPql737o/7J3+Gx7lLQt+r78s8/qTqdtkt+qvg+pGu77azwt36+Ttse+K8sTtr36jvQ/kHP48OHw+eSTT4bP1Jo1a8JnWVmH4fDFF1+EcnjFihXhPJ+67rrrwufp06fDp/zwww+hLqDpfNntdSqQ4fPSpUvhU1599dXwWZYnt27dqovc4RPDqRNghM/ly5eHz9Tq1avD5/fffx8+e/XnP/+5OHXq1GgdxHvnnXfCZydoyx4TqqMon548eTL2Kbdo0aLYNWbv3r2hXvPss8/GPgMqhFMYpV1iqeqKu10tUEqjaX+bNJcUveei+/QORZr8dFpmbhwlvz7+akNZSq962dUwpdyVArsKoaTt9OwqSVnKbXvVOqp/2fro+/Hjev4Oka6ElH0f6p9eSaz7/pTSq0QTcUdK+07LbqMuz2ieKT+8Km/4K6hN8lvV9yFVw33/snWy76psOFdvkWP5o6o8t3HK7ioAVgb6crEJm85f7bf8BvTK6hxN6xs5/o5qrny0vFtVdubk1svuSFkdR8vWOT1XRxk0HMkJy1RlmUdfvq/YK/mCVUFBXSVcKb0dm1Yyy5JlOsvgueQzcFVF2Se/Df7gUkorFz5Y8geB3wYt16ZLK/tpEJLuz6rkty3dZ54PbOpSWgH3+9b2SxrsKZD2egmkyvKK5q38oWWn+95rmmfSE39unLJkx0CT/Fb1fUjVcN+/KvkLGLmUBumA5Q3Lyylf3pWNg+GlC4dW/ukc0KaMsUejlKwCaeWg5iU6H/pzi5Y1yO+LYPIpD9q5MD2/t2H5uiyYsTyp5SnfWjCkpDzrLw54lp/9saL1VX3HWD2yqo4zKAikEpZJmiZlDJ9ZlKn9MCsQNU5aufcZyFdUNZ2d0DWOL2TT6Xz/tBKQu+Nh02pcP990O/wwf6BqHOuv5O+g+IMsDZZ8BdgffOn8tNyqbbdKu2g8P8xL97Xm47dd22vD/Dz9iU/r7KX70+slkBLlD78uuaR1z51Y00LNX+nxw9LtsP6WlC/su/f5V0nz8fywNL9VfR9SNdz3V7I8p/XyeUfJf5fp95yuE2DHQlllwech8g9MWhaq3PHnyDoaV9No2tx5S/2sMqkyTv+XnScBz/JNWm9rw5+P7XyasuFW99HylE8tXyvl6juqr2iYxlM+1jj6387rVs+aKU+REEglLHM0SSr0fCAhlmGUcgWhz4A+QLF+SmkQomVoOmW6dHl+urQS4Ncll9l18Pjp/fr4oEHLNr5/WkEv408oSn6/2AFnKT2gNW1Z0OMLAiXPV46U0sLGCiKl3L7JmYxASrTNfn3KUloR9MPS717b64f7fOP759Y13Xee758us+r7kKrhvn+6Tun6+G1JtzNdJ8DnO1/GSXohg/wDo3JHZZGS5Q+dx9JzcI4/56WV3bQcTPOk/rdh5EekfF1hPPmj7gKT2HJsvDQfW9mpYyWlstUuDOjT53MdU/648OOqf25+/ezK2s6Qs0xTlVRA6ovPyY1fliyzpAWrz6x1/HTpQeWHpYW18ScJf0BpHfz0FuD4Ox1lmV3Tav/YicjPJ51O3da/LDDz81C3Sfeb5+frA0Hjh/t5ejphar9pv9hB7pPXZH51bL8pYPaBp0/2HafbXpd83vD9/Xdh0nmXBWF+npJOl6oa7vun6+T3rVLKD0vXCRCfh3Qs6xi1Y1rHt5Ux5B/k6PxnZbLyTdU5WsN8EJUGXr4czJW/ojyp4ekTARhuli+U0gvubfiL6FVlno1TVqexi8vK501Z/re8b//ruFI/q2MO0t0qWu2r0PmCVWsrOpkutFpi1MLJhx9+GP/r3aeffhq7uuVaRxmvG2+8MXaV8y3YaR38Nh85ciS0lvb222/HPmOtXRkNV0t38+bNK+65555i06ZNxaFDh+LQemp9bTK03Z9qMU7rcvPNNxdPPPFEsWvXrpAHJpvWU63gqKUmtYLTOSEXnUButPUeefnll2NXO59//nnsak8tUwGDTK1R7d+/v+hUCMKxrHJJx1WnIlDs3LmzOHfuXBjvqquuCp+Apxb5Dh48GLqVf3Q+zFELqkuXLh1tBU2fCxcujEOvpPyY8+CDD4ZPf77F8FLdSq3jqi6ickt1U7Vk2yvLv53gpbj99ttDd5V77703dnWzdVDLe01bM37qqafCcq2FQKvTqHVV9VPrqTp2tm3bFrZ7EBBINaBCVCfbTqQc+xQhQ2/ZsiX+l6cTtwKxslTW3G5Zk9zj0aQinTbfaoW5qLlWf/LQCSAd/6GHHgr7xehg2Lx5c9gP6q5jlZnppMJAQaAFTiq09L0roFGaSNa0t1KuqXIFVo8//nhXQFvW1KmCrlwes6T59GqiKpfjCeaA8dJFClWG7ZjQxQpVBHSytuO9qtKL4aby2AIf/9MVRufzO+64I+Qljae8lmsS3Zen5DfUseBcF38UgBw9erRR8FPl/fffD5+PPfZY+CxjF3GbXIhvQseILi4899xzsc/IxQItxx8r9913X/jUTxIMAgKpFv7yl7+MZixRxJxG4T5gaHrXKj0oTpw4EbvG6Dd1dLen7LeBcvzVLjtwPAVs/o5RWqhrvXTgijL/iy++GLrlkUceiV0j0nkp6FBFRXdXVIEpuyt00003xa6RK31pEKlKTm5/TJY333wzdo1crfnyyy/Dwa9AZKIKE+PzyksvvRS7rmSVPO+GG26IXSPKrpDWeffdd2PXmOPHj8euEb2e7NPvMvcbWMB0s2OnycUezFy6MNrrb9LpHLFu3bpwZV4XvhRElZ3zVJ5aPaLuKr6vb2D46JxpwbnKp08++WRCgm+rq5XdETX6TTVJ6wQ5dRdcVZfT70VpmendtFtvvTV2DSYCqRZUMP7tb3+L/41QQOFvP1okLbo7ox/gteHq9nchfMXSZ2gfMGla/a9ARvPT3ZKyO1l2xd/m64MdHTiaj1VuVYD7O2wqsNNH9cRfsdA6iMZNfyTu66+/jl0j/Ly0DT7I8nSlxdM62clF26Hb2To5TRVf+de6+JPh3//+99g1MXxe0f5R4eLzhLp1cvePd9x5553h018dlVyesXymH64to+/U5wvlreeffz50i88jqTS/pV544YWwLkrK+/5uJTBV7Me5yyrIdoHol7/8ZfjEcLr22mtDhfWVV16JfbqpnMtVQFXuKogSXUDU0yt1rCJZ9qi2XdBLK5wYHjonK4hqEpy3YfUr1ePqgrKf//zn4VPHhM7jKauL6qJz3bz047s6vtIf39V6TOXF8klxGV20SyyVvYTXqVx2jedfitOLpp2M0TU8lzoFcZxihL1wV5c6GTZOMSI3jp/34pJGC9LUOQHEKbp1Mv4V43YO6jh0TDqejaP+6f5KX7DV/vPDq5LftnSfef7l8nRfS9lwrbf11/doLwrrpcr0e/XqlpfjX0pukrR8TWOa5pl0f+fGKUvpMZAbx29vk7xvyfP90/X1+1Yp5YeVHbMYXnac+ONZdCzZ8Z6Wqxg+/tytfOHLWuUbK6t9eeenScutKv58mU6nc7EN03gYTspnygNN6xNN2fm06XxVNmp81ePS+ofl/bqGL+w4yS3T6oe+bLZjzS+vnxFIJfTlWSqrlPnC05LPBOpOh/ukTJLLINYCSlnSPP1yJA1SlDR/o+XUVdbrTgB2QFsq2y9VAZEdjErpwVS1jurvl++DOKsgWfJ85Tt38JYN14mr7LtTfz/M74e65ZXxJ+iqlPvupS7P+P1l/HAtu2x7c4VjXX7z+yFNPkhV8nz/ND+m80z5YWV5E8PN5z0rUyzflx1bGD7+3K1P5RNfPqvbn7uryrs0peWavzhny/LnybrKKWautG5TldL6hv5X/zS/Gaun+RsAVXRMpPU3f0zk6hgpK39zFwZsW7UMrbPVMZquXz8gkEpY5lCqqpSpmWo/rq9MijKMMo/PgBpHGSUXRBllWk1nBaxNp0yVm079/PhaXi5jq1C2A0xJ4yvDNql4+sq65l9F25cedJreX4FTSg8obYefVutnBYFfb+snaWHjaTzrr+lTVcP1HfiAwfapfafW3+/nuuXVse/Hf+/qVj9doazKM9oPWl8/raYrOxHbOEpa73R7ld+Uv3Oa5Dct1xe0fl2sn5Ln+/vvWPy+VUr5YU3yM4ZTmi+Vd5W3qo4tDJ/cubusPFV/G6cupeWa2LKsPNVn0/MyZq70nFeVlAc9y5O5/CZ1w3PS+pktt6yO4VndL60neMrvVjZbuTxIZulPZ+WBvqX3pOzZ9M4BNtpsJnqj90UM+xMAAKA3NDaBaWeNIiip1STf4IMaKfANVeiFYAAAAGC6EUhh2i2ITazL+fPnw/8WWOkHcc3sTGuBAAAAwHQgkMK0q/oNJU/Nyk5E858AAADAeBFIYdrpB3t1J2r9+vVX/Cim7k6p/7Fjx/hNDQAAAPQNGpsAAAAAgJa4IwUAAAAALRFIAQAAAEBLBFIAAAAA0BKBFAAAAAC0RCAFAAAAAC0RSAEAAABASwRSAAAAANASgRQAAAAAtEQgBQAAAAAtEUgBAAAAQEsEUgAAAADQEoEUAAAAALREIAUAAAAALRFIAQAAAEBLBFIAAAAA0BKBFAAAAAC0RCAFAAAAAC0RSAEAAABAS30RSO3YsaOYNWtWbbrrrruKLVu2FN98802ccnp9/PHHYX0wMbQ//fet/9vQ+Bs2bCiuv/76rvko3+zZs6c032i4jau8OBP5Y0zb24bfP22nNW+99VbxwAMPFHPmzBmdl74n9dOwiTae7cXMYfmgrixRHvT5XHlT0/bLuQZTR995eh5ROVWVhzSN8suSJUu68pDm89VXX8WxrpRbluYxGWUiBs+BAwdG80VZ6qWepPxs0+ucXJdPz54923X+bjKN8rDla32qDlbGtnNg8/3lPrB9+/bLWpWmafbs2ZfPnz8fp556Fy9evLx+/fqwLitXrox9MV7Hjh3r+p71f1P2fVQl5ZszZ87EKcboO7RxlBdnIn+Mtc2zfv+0nVb7e8GCBaPTl6XFixdnv5tejWd7MTPs27dvNA9UlSW+7FBeVX5RWWH/T2S+RH/Td23fvT6VF1Q2Wf5QnkqpPuDH0TQ+D+lz//79cewxdctSvsRwa1I3blNP8mViWtbpM1fW5aaxc3rZNMrvGq78rG3QNPq/rH6l+SkNqoEMpJT0xUwXKmmTo9dAavfu3V3TVSUd+DrxeXaQK5Ud6INuPHnW75820/qKQpOU+256xTE63NJzSllZ4sdTOeJZgKXKAIaDlXX67n1ZVBWU2zTKJ/4Cr7/gmpZt6rbKaLosfx5seg7EzGR5KxeIt6W8afnKl3U+n6bBjIbZObysfMydt+2CgO+veWvclB1bE7GN06XvAqmySo8KFH+1Rmm67kpRSZsc/gSi1PQkYickJeURf0Aqj6SVqrRAQDUrzJWa5ncVoP57Udq8eXPXMavvyc9bSd/VROAYHU6584RSWVlilYSyfGf5M3cnAjOLLvzou85VDMUqjirHjK+cltVHrBz05x11q19Z2aRlpMvC8LG8lcuPbdk5MZfnNH9bli8r6/Kp5e00CMpNs3bt2ivmr+XqeCub/6AYmMYmbr/99uI3v/lN/G/E119/HbvG6FnL9Fl3PcupZzzL6Dllvevkn1O26fwzoHq2VMM2bdoU+xTFoUOHRqexZ1X98vXcdKpseNrfnku1fnp22j8P659BtWdWe3mmP30/wJZV9o6AH1frkz5zq3Uqm1bS8cf7THjnBBa7iuKPf/xjsWrVqvhfUcyfP7/YuHFj0alcxT5FcfTo0dg1ou77yn0Pymdi/ZT8d5P21/iazvppfpa3tJ+0XHv+2PZflfQ707Sap18HT/OzcTVdytYhzU9Vz0BXee+997q+l06BXGzdujV8H0bf08GDB4tOIVp0CtmiU1ktHn300Ti0W9vtbULbpm20bVaqyvdalo2ndUn3mdJ41wm9035ftmxZcerUqXC8dyrGcUiejuvvvvsudJflu0ceeSR8fvDBB+ETM9cXX3wR8s2KFSuKuXPnxr5jrrvuuvB5+vTp8Ck//PBD0alMhul82eapbJNLly6FT3n11VfD55NPPhk+UyorO/Wz8InhZHVW5a1cfuzVLbfcErvGaP46D6cuXLgQ8ve9994b+3TTuU8+++yz8Fll0aJFsWvM3r17Qxn87LPPxj4DaiSeml5Nrx772+tK6VVGu2JUlnJXFeseP9IwewZUy8uNY8nWR9tg/XJXOsuG+/6dg2e0O01aTtm2aro26vaZ5pdeDfHrWTV9bl3S79CndJvT77eMv/Ohbi2jzRWcqu+ran2r8qPvX/ZdKm/pKmbZ8NzVSG1X2fiWctNVHWNV89Q6+v2bTlvGz0/T92oytleqvlclrbMd98Yf/1qnqvUa5McUBpW+H33X+m6NfR+5ssR/n2VsnPHkYcwMdp5o+0SDTefPLXX5DrBzlM4zykO+nqq7O7kyrYrdXcqVZTrP2rzT814ZTWPrlE6jful51+5I2biq+2h61SEH3cAEUqqY+AqdvgDPz6Mq+S/cZ4SqZBnPn3hzyTK2FZxKvvA0ZcN9/6rk90MuNa3E+e3RwWqPJqSVTF8xkabrqeTXRfPPjVOWmhYUZd+91lOV7Lr9UfZ92IHu51mV/PrmhudS3XepPOrVBRWW0pO930faXq8umPYpnbaMn2Y8j6dMxvYqP/hpy5K+G7//645/n7TemH72feTKEv99lvFlIYaTygs7R+i4TsvkKqpvWP6xuoflOysjlMd8OadlNT2HY+ZKz8vKF0q+TpLWzaoo31o+07ytvqd8af0V7NTRfLRcq7vkAiGbnz9WNL6vt9v22XoMsr4LpJomX+EVn7l8JlGh5Qsp/6Wny7XKmL58+5It+QxbVUkTK3SV0vWUsuG+v5LWwTKiRfOWtL1WOfAVAqXcMnP8PNMD0lfw0/lVradd9bDkp1WFOh1m02n5adBi29dEuk5p0rz9enpl30fV+qbbqeTXNx3m81YaPCl/Wn7VMvwwP0/tIz9M21OWz7W9flv9fLW9RuNYfyXNw5apeaf5zk9bxlcelPw+bWMytlf8/td0VmnR9On+9+uuZfphmtbvK78+Sph+9l3Y95TSd6jhaflnfNmA4ZKW8Tq+fRlTR+NameDLICtH1E9lmrpVJun/qvMuhovqHyqfcvUWf54qK9tyNJ/0nG6pSX5Lp9W65djFSuV/zdfKUasHWR1hPBdZ+8lABlLpzk8rOCl/BVoZ0/iTZC5DKBOof3p1yK+vLyCNn28uc5YN9/21nv7gSbfRMqTxlbjcMtvwJ4Dc/Px6arxU2cnAzzO3v9OKc5sCQjR9GqSkSfvVrgyasu+jbn01rg1X8uvr+2v+XjqdXx/tez/Mz9OvZzpPUWXeT+vziF+mn9YfG0oWqHh+n+aWm0rzqt+nbUzG9qbrlstj+q5tuC8v0mnTciHNv5h+9l3kvmexfKLvOR0nPU4xXPT9q+zw5ZDOCen5I8efQ9uey/W/DSvLt4Cdp3J1sDK+TNN0ytt2ftdnek5LKZDSNL5upH4+fxvNy8/b53PNwx8Xflz113oOkoFpbEI6Oze8wJ6+gHn8+PHYNcJe/LZ0zz33xCHF6MvFooYizOrVq2PXmJMnTxY7d+7sarxgqtx6662VLxjeeOONsWvEeF5G1EvzagxBL87rJfp58+aFF7ab0Iu5KXsBMeXn+bOf/Sx2jdE2j4de9D937lx4ybxz0IaXfDsHZRw6Qt+/byykSt363nbbbbGr2p133hm78hYuXBi7qr9Hn19zL3/qZedOARX/G3tZtYp/SbRTkGVfmM59x1NhMrbXlxXKG2rEJvXggw/GrpH8UtbgxtKlS2PXiGuuuSZ2YVCoIRrlIX3PaqhCjY2oDFRjJionOsFxHBPDRnlDjeEoqd7RqTyGc8IvfvGLbGM0RsOUhzSuyhg1blRWrqtO8/jjj8f/Ruj/TiU5dL/88svhE0jZeappXU0NqqlMU57sBOihfqu8rTqT6kvK46orVzWWpEafNI2m1Tw0r7fffrv41a9+FccYo3qz5t2JM8Kn5XPNX+f23/3ud+G40P9WR9fxoPqG1lPrOyj6LpDSSU07XqkTpXZVhJ9//vnQSs545SpcP/rRj2LX8FCBr1bLFDgpIyvz+sprE1dffXXsaidX6Sxr9agtBSY6aHXQf/vttyGw8hVubWOTSrfXb5XkNJDOadviXlkAbK1VNZUGJ761ql5NxvY2DdxzrYPKeC5eoH+oYqATuFWUVT7oZK6KguURfx7C8NG5SflEVOE8cuRI6E7pvKILLMpHlp/8hbKUPy95VklWJRXIueGGG2JX/UVE1fW2bdsWuv/2t79dcY5WfUlloDz11FPhs47m8frrr4du5dOm51/NXxdtdaFC7GLB4cOHQz/V23TsaH2rLlj0k76+I6WI1jdVrauGd9xxR+UXpi/AArGylCvY/vWvf8WuyXfixInYNb0eeuihYteuXfG/kX23efPmEMCqezJ9/vnnsWtM24qw+Ga9dTU5R9/3G2+8Ef8b0TYgn8r80URu/6XaBqZl+fKf//xn7GrO55+JqAxM5famfvKTn8QuzFQ6gesqq50jdDJXReEf//hHGD7eu+UYfLpwYoGPmoVOKc+ofqJAS+Mp8MqVSVdddVXs6n4aAUhVBUj+AmXdhV417W9yT2GI5e2md7jEP61VdsHR0zGi+T/33HOxz0j9QBeq/LFy3333hU+/3v2s7x/tU0FjkbIomNJdFO+mm26KXSOZoGmF3F8N+p//+Z/YNUbL0eNi+vJ7jYzTSqjWTdsw3bQe/u6Tbu2qIqHHJnVwTMbVdr+/099yEv32UFvpd192W7qXQMgHA7n8kT5SOtn8/nv//fdj15j0O21ykvaPJypfpgW38r3yf1tWEIoqFnv27In/XUmPweg40zj+2J2K7c3llzfffDN2jdyJaBugYeb48MMPw2fut1cws9hvSeriXFsqI9etWxfKFD2WpyCq7ByqcsrucFY9RiXcCR1OOg/r4vDNN9/cdU707CKP8shE1Nd8gG/sMee6fNqE6hL6vSid13W+9wb9QtVAvCNlz7EbVZ58xUy30n2Bo3djrEKoTJj+EKrx767ozozmaQGTutVP0bIKyN///vehf0rPfmoaLScXbKmAtUyoddK69YP06sGaNWti10iG9xXUieL3t/ar/+FT7Sc9utlW+t3/x3/8R1fgq0+9/6Xn2o3G97fFy/h3g5QXbH2VlD+avms1UezHQUXfj//BXOUxn7e0jf47LaP94PffL3/5y9H8qnnr2edeAn/9wKmf7xNPPBH2nz8p2I9na1uUHzTOCy+8EIdOzvbqapweKzDKL/bjyvpetY7+Lq2e48bMpfyn80KuoqC8ZhcR7r///vCJmevaa68NF31eeeWV2Kebzt92XvT1EZUfqiOILkjqveo6Vg8pewfKLuakFU4MBx9sl11gfumll8Jnkzzi6zu5sk5sOf4C8o9//ONw/vcXFz2rh2tdy+50Gf34ro6v9Md3NW2/PKXVs8t9YLtrSaRTQMW+3dRSjo2j1Nn5XS2M+XlUJd8KjloM0Xxy46WpybJs3mqdJDc8lzQvo223/ul+0Lz9dH47xE/r51lG2+PnZ63SqX+ngto1LJ1f3bLKhrfZ30rpNpZJW0urS023R/ui1/X1/dPl6X8/POWHpfugU8h1DS9LyoOeX2aat9L1qUrptFV0zLbZf+kxLZOxvWohyE9bltSKUFVrW6m64Zh69l2UlSWWT5TP/HetfGh5z8pGzGz+/KTv3OcHlWWWH3x54qdRXmrKn3/T6Xz9IS0PMTysbFL+0jnLKM8pf9own0+r2M+5aJq0PPR1KL8sf05Lz7Ear2net+MkV3+w+qaOMWPHWtNtm24DE0iJH09JX4BnmassKbOkmlT20unSoM6SZUBfuKZJ/X2g4jOgtt36p/shraSlB4Kfti5TGzuwcsmaolRK16VuWVXD/cGXprTSXFb5yUnzRlnKVYqq1rcqSEv3nz/p+f7pPNN1Tflh6T5Q3kr3U5rS5YlfZvp9it8HafLLy01bRceKz0tlSeP4gtRM1vbWBd9aZro+6TGYqhuOqWffRVlZkuYv5RV/LGjYoJzMMX6+PqBP5QWfP9L8kJblVSktp1QGpcvyZWWuvoLh4uu0ynvKIz7P5M6ZVn6l+U351pdtymtpnkt/Wkj8uTI3Ta5OlbLtyF0YsPOm5ql1tvpxbl361UAFUuILNSUfPYu+dJ9ZlNn0xZSdSEUZTF+azxzq1pefy6ii5fp10TL9MpRhNL1lepuf+vvt9Zndr3e6H9JKWro9ftr0AKqicf12az7ah1pP66fkD4C6ZdUN1z71waQdQPoerJ9S1XeWY/s8zSP6X/3L5le3vprOr6/G1zak34nn+6fz1P9+eMoPK1vntvncL1PT5Wgcnxdsfk2mraLv1dbXjgclLUvL0LA6k7G9ll/8NiuvaFpfWTJV37fUDcfUs++iLJ+Ivus07ysfNMmXmHly5YLKkFx+8GVSXVIeS9myrFysK9cwfNJzn/Kl8oyvk3k2bi6/SdtzqWiYxukln2o9NY3WuYzmY/U2bV/ZuverWfrTWXkALelZY/32jOFQAgAAGB4D9YO8wFRSwwPWSImS/jd6Ed3/3sIC14ABAAAAZj4CKaCEWnHy1EqfBVUKnPzvLTz22GOxCwAAAMOAR/uACmo6v+4H6hYvXlz5uyEAAACYebgjBVTQjxTv27cv/G7IbPe7SKJ+u3fvJogCAAAYQtyRAgAAAICWuCMFAAAAAC0RSAEAAABASwRSAAAAANASgRQAAAAAtEQgBQAAAAAtEUgBAAAAQEsEUgAAAADQEoEUAAAAALREIAUAAAAALRFIAQAAAEBLBFIAAAAA0BKBFAAAAAC0RCAFAAAAAC0RSAEAAABASwRSAAAAANASgRQAAAAAtEQgBQAAAAAtEUgBAAAAQEsEUhi3u+66q5g1a1Zt0nhvvfVWnKrbjh07usabbH55Sm347Z2KdQUwfh9//HHxwAMPFHPmzAnHrj43bNhQfPXVV3EMoCi++eabkC+uv/760XJe+Ub5p4ym0TllyZIlo9No+rr8lVuW5lF2nsTwUV7wdQ6VW3X5Mcemb5Jycvlb/ZSHc7Telq/1uWfPnjjkSgcOHAjjDWy+vwyM08qVKy8rKzVN69evj1OO2b59++hwzW+y+eUpteG3dyrWFcD47Nu3b/SYnT17djhuFyxYMPq/hgNnzpwJ+cHnk8WLF4/mnVw+uXjxYtc4mkbJz2f//v1x7DF1y8qdJzFclAcsPyhv+HJLSfWYpmyauqS86JXlb/tfwzSOp/xuw7SONn7Z+mqblAYVgRTGzR9UTVN6QiKQAjAZjh07Nnq8qmLiT/oWYKnycP78+dgXw8rK9rJ8oqT85Nk0qjT6PKTprSKs/OXnp26rEKfL8vk1XRaGh9VRlHfSfLB79+4JzSM+qE/nt3bt2tA/zd/qtjycBkgWePl8rXHTIE3s2MpdbBgUBFIYNx9YlF1x0EFiB6pSGoAQSAGYDFYRKDtWrSxQhRbDS5VJ5YM06DEWFG3evDn2GalMqp9SWSBulU1Vfo1VhMvypJaRLgvDxfJN7i6oWH5U+TYeyusW+KT1t7pjwt958tQvzdtWDvtATfPUvAe9HsU7UpgSq1atKn73u9/F/9pL32+w527rnkHXM7f+ud6mzxbbM+/2jG+b9ynOnj17xbsY+l/PAefYuilpHI1r/6u77BlkAPUOHz4cPp988snwmVqzZk345L2U4fbFF18UnQphsWLFimLu3Lmx75jrrrsufJ4+fTp8yg8//FB0Krxhuvnz58e+3ToVyPB56dKl8Cmvvvpq+CzLk1u3btXVvfCJ4dQJMMLn8uXLw2dq9erV4fP7778Pn73685//XJw6dSrk4Y0bN8a+I955553w2QnasseE6nXKpydPnox9yi1atCh2jdm7d2/x3XffFc8++2zsM6BCOAWMg64mKCspld2RErvKppReRam6I+Ufq8glXdHQlZOUXbHJJbsCY8nzV2jSpGXZlSKltuuau+rth/t52/8AemfHUtUjMDZO2V0FwM5z/s5SEzadPzdafgN6ZXWmtA7Shr+jmisfLe+2fXwwt152R8rqalq26lO5OtGg4Y4UpoSu9u7atSv+VxQPP/xw7KpmrRqJrtB0DuhwBaRzMI5esdEVjbRFmHR5KV2BKfP73/++dLiW1SkA4n/ddKdr3bp18b88rVNV6zXpvJ977rnYBWAy+LvMX3/9dewCRugpAbWadujQoXDV3u5gNqGnEzSddCqW4dOeiNC8JH1qQssqe3oBENWLXnnlldB97733hs9eWN1Kd5xuv/320O1Z3r3hhhtGnwqyfKo8q6d2cpS3Na1/mkZ1KtXZFi5cGP5/4YUXQn3q6aefDv8PtJF4CuidXbVomnLP/JbdkfIvVaZXLvwdp/Tqh7+jpKsetkzdbfLLsmQ03PfXfOxqjK6g2FUVS365fpim81de/LD0LpP1t9T2iieAcnbslV359OVB2yuvmLn8uUdJZXruPZEy/skGf55QHrN+dg7TOUH/+ycS/B0swLN8o7pNmzzpWT5UUh0lx4bbkzZanvKpr1/5vG3KWu2zuo29ezVT3gEkkMK42UHSJGncXGWlLJCqUhZIpcFQLnDz0yoZKwAs5QoYf7Lzy/XTpduYrpN/FNH3V8EDYOL4CkN6kSJtBCdXNmE4WQVQyfKHymdfdpfxQVRa2fX5USnNkz6AIz8i5esu48kfdReYxJZj46X52MrOXNCvstXqSvr0+VzHlD8u/LjqP2gXEQikMG7+RNM0pcFNk0BKB67GUwHgKz/pNOmJKhcM2RUWS8avhw7snFwAly6zLvkC0PcftAIEGATpca3j1k7cOp6tDPPHJWB0DrHASPnGVyhTaRCVBl7+XFFW3ts5Ruc6wPi6R+4CcVPKzzafqjLPximrk/k7VU1Z/re8b//ruFI/C/AG6W4V70hhQnUOBEUlV6T9+/ePPhMuepeoSQt4oudw1fLdsmXLik2bNhVvv/12eLa2qVxrStdcc03sKqcW+3Ks9abx+Pzzz2MXgMmm1qhUBnUqBOE9RD2/3zn5F52KQLFz587i3LlzYbyrrroqfAKeziEHDx4M3co/R44cCd0pvRO1dOnS0VbQ9GnvhOQoP+Y8+OCD4VPnOkDvGundOb1jrXKrE3yE95V6Zfm3E7xk341Klb2HZeug+liT1pDlqaeeCsu1FgJffvnl8KnWVdVP7wzq2Nm2bVvXO1b9jEAKU0LNZP7v//2/438jyk5GnoIoBU8WOOkAXL9+fagA6bMJndxS//rXv2JXuRMnTsSubv/85z9jV7mLFy9mA0pLjz/+eBwTwFRQGaTKsB2DarLXfl5AlWOpqvRiuKn5Zwt8Lly4ED49VQDvuOOOkJc0nvJa7iKeD9bJb6hjwbku/qj+c/To0UbBT5X3338/fD722GPhs4yCNrnxxhvD53jpGNHFBd+Ili4WaDn+WLnvvvvCp36SYBAQSGHa+N/VKGMt08jatWvDlWNdQVYFqOzOUFrI/N//+39j15jXXnstdnW77bbbYtfIVZY0CFOlS4VBSq3aeE2CRADTz45Vf8ccw2fLli3hKYSylsiq6Jygpyx0ztAFPgVRud/dEQVPVkGtu4pv42E4qf5hwbnKp08++WRCgu+0Jcky+k01OX78ePisUnc3X3Un/V6UlpneTbv11ltj12AikMKUUIGgW7reTTfdFLvK2ZViSZtMf/fdd2PXlXwB8cwzz4wGPzqYdaK0giSlgMifvH75y1+Onuz0KOKvfvWr7GOF/mqlqFlRa8JWy9T/1myoHlMEMDV0vOu4K6sgv/jii+FTxzqG17XXXhvON/7inadzWK4CqnLefvZi9+7d4UJfHatI2mNNqTfffDN8phVODA/VNxRENQnO27D6jOo5dUHZz3/+8/CpY0L1mJTVq3SnrG5e+vFdHV/pj+9qPcqe/hkYl4Fx6pxUwsuBbVLnwItTj/Avg2t+RuNZ/8WLR5qfVfLjp9OIf6G3SfLSeVclv9ymy9T8vaphAMbHjsvOCbvrxX+VI/bydloeYfgoPyiPKD8oX+h/o3yj84+G+TLfT9Om7O5UKMM0uel8q30aD8PJ6lVp3Wa8rH7TdL5WB1MjEP6YULlqeb+u4Qs7TnLLtMYlfNlsx5pfXj8jkMK42QHfNKUVGrGDW8kfbGoW00/rkw+ylFJ+nmmyA9VSqmqb/LRpwWCt2JQlnaBTfnibkzGAZixgUtLxq+PWKgG58gjDSfnA5wvlE1/eq9tX7qrOMWlKy3adK9Jl+XNaXeUUM1ebC8FpHUT/q39ZXUKt4Wl401bxdEz4fJkeE7k6TcrK39yFAdtWLUPrPIit9hFIYdzswK1LOvh0QOUOJn9CSgsGBVPpyUzj64RWd+LJTavx0oIqR8vw89cBrumq1lU0jsa1k6SNV3ZitHGUNG8AE0/Hny8L7MQ9KFc9MTV0ftJ5Kq085srvpuc+pVzZbsvyAZWdZzC8fB2jLqV1EMuTZXWJuuE5KiM1fpNjIqU8rvGrAi7ldyubrVweJLP0p7PyAAAAAICGaGwCAAAAAFoikAIAAACAlgikAAAAAKAlAikAAAAAaIlACgAAAABaIpACAAAAgJYIpAAAAACgJQIpAAAAAGiJQAoAAAAAWiKQAgAAAICWCKQAAAAAoCUCKQAAAABoiUAKAAAAAFoikAIAAACAlgikAAAAAKAlAikAAAAAaIlACgAAAABaIpACAAAAgJYIpAAAAACgJQIpAAAAAGiJQAoAAAAAWiKQAgAAAICWCKQAAAAAoCUCKQAAAABoiUAKjW3YsKGYNWtWV/r444/jUJTRPirbZzt27Bjtf9ddd8W+ACabPy6BOgcOHBjNL2WprGyvSxoX8HL5pCy1oTz6wAMPjE57/fXXh7rdN998E8e4kk0zZ86c0elUX3nrrbfiGFfSMM3blrFnz5445Ep2bFXNr58RSKERHWS5TP7mm2/GLgAYDCrPHnnkkfgfUO+zzz6LXRPv6quvjl1AO7Nnz45d9VSHW7ZsWfH2228XCxYsKFauXFl8++23xa5du4qf/vSnxVdffRXHHOOnUSClaRYvXlwcOnSoWLduXfYCsAIjDdO6bd++PQRSTzzxROkFgyeffDKsj4K1gXQZaGDfvn2XlV3S1DlQLl+8eDGOhZxjx4517TP9bzqFzGj/TgEV+wKYTOvXr+86JoE6Kp+VV/bv3x/7jI/lQcp9tHXmzJlQ91L+8fWJKufPnx+dZvfu3bHv5VB/s7yd5kVfd/HTiIbZ/FSP8TqBVujv64adQCmMn7K65UQdV9OBMwgaWbt27egB5buVdCCgXFUgBWBq6YSt41AndjsmgTqWVybiwqFVHrkQibaUXyxQSQOYKps3bw7TqP6W0jwtKFKQZizY12eOz8ee+qVBmdUbff3HljvoFxN4tA+19BiMbuuahx9+uOgcFPG/onjttddi15V029eeqdVt3dzzubnbvf79BSWtg8azZ26VNJ+zZ8/GKa6kYf65Xn3qf912zvHrquWXrWvZs8Tp+EuWLKl95lfzs/H9LXK/Lkr+lru2yw/TMgHU03H0//1//194jOSll16KfYFqdp7RI01z584N3b1SHtQ7KfL666+Pe34YLn/+85+LU6dOhby4cePG2Lee1eFUf0spD1o94p133gmf0glywufq1avDZ2r58uXh87vvvgufVRYtWhS7xuzduzdM++yzz8Y+AyoGVEAp3dJVVlGyKw92VdeSbhvn2C1jJbuKkkvpVZL0Lk7ZtFqf3B2eskcRLeWusPh1TR/98UnrkqpaXrrufn3LHu3T/vTT+P3j11NX1bmiCTRjx46OQV/GAFWsfFdZrjyk847lHZXNuXNQGR7pQ698vaBNnhObrqyuZvW8NvmyrAzNzcfuSNkdL3vUsOxu1yDhDIJaPhDwmd6fTMpuMVvFpUny8/AHaF3Sevhgoum06TO/bdbVP8+bBj11yReAZYGU+GE2nQ9qrR+AenY86REX8eUEUCW9sKayWsmfAxVs1fF5rqxCC5SxOkrb4KNJWWfj6OJsUxYcpRfCrc7o62XpO1J2TM2E44BH+1BJjyHoNrLxt3j9I2WvvPJK7KrWOcCKzoGjo7noHLhdLc48//zzsSuvE0SE6ToHZ9E5CGPfkdvK7733XvyvKF5++eXYNbK8M2fOhOm03M4BH4cUxX/913/FrjwtQ8vStFq251tw0u1pr1NhG52uc3Jt1aqOp9v2Wn/z1FNPFc8880z8ryg6FcLi9ttvj/8BKKNHszZt2hSOp61bt8a+QDMqw5XsnHDw4MGQ1OKZyntRK2V6vLvKc889Fz41n/nz54duoAnlLbWUJ08//XT4nAyqJzWh1xbsccFf//rX4dP88Y9/DJ96RUGvL+hT8/3Tn/4U+qs8VkuBqsPMiOOgU9kDSvk7IP5qgvirHEr6P+Xv8mh6f4VCyuaR9tfV5JSft7qNny5dJy3fD/cvVvr56YpKyr+c7tdH41p/XWVJpY/9+XWyq+RKfhtMuh8s8Ugf0IyOE7sa6o93f2wB46FyX/kod94wynuW32bCVXhMLbv7k6tj1GlS1rUpD32dJlc3Ez21Y3UmffongFTX8fVBP676l82zX3FHCpX8XZu0UQPdDelk/vhf/W9K3XrrrVe8WJveUfn8889jV7fbbrstdo258847Y1dRnDhxInymVwT1+we+YYZ58+bFISN++OGH2NVtxYoVsWuMGpvI8Xfsfvazn8WuMdruXmn/6KpNSg188JIyUO/3v//96NXQhQsXxr7AxHnwwQfDpz8XpOwHSTuVSO5GoRU9GWR3fyyvTRfdidLdV9Gd1bIGL1atWlWcO3cuPJmjz8cffzz0tztrv/vd70IdRv/fc889YVgngAp1Lz09sGXLltBvEBBIoZRuv/rbvLoV64MSJT9cB1hZi3ZNXbp0KXa106TVmJyywK3XH0i85pprYteY8Z4077777tg1Yvbs2cVPfvKT+B+AMmqhU+WWKq92Igcm2g033BC7xlr4S1kLrvwQNNo6cuRI+NSF614e57/qqqtiVz1/cTyl4MaCKL3usHPnztDdhl5R0DIsALNXMQ4fPhz66TjRI9jbtm0bd31yqhBIoZRvBrMJBTN2wPeq1wBGwUXOxfiuUlma6MpVLjDzTZf3QgWPp/1szecCKGdNnOsKaHoRSHerjfWre8cFw6ssQBJ/ATB3MU35yi728XMVaOv9998Pn4899lj4bMvfiS8LTqzuknvyRtPoPScFN6pr6d3vXupOCpJ019beFRTdadM8/QXn++67L3x+8cUX4bPfEUihlP/tqKaqflNKlZn0IE4rLjfeeGPs6vb3v/89do356KOPYtfY43P+yqCMN7BrQle7zdGjR2PXGN8QRlt6UTP3uIj2pT0qAiDvlltuCcdnLumqp7F+ba7cYjgogFKQffPNN5deFPvHP/4RPlUhzD1yffz48fDpGzsCmrJGJlRG9crKu08++SR8puxCgcpMz4IorYPyt+o4vVwM0Hz0e1HahnT68bz+0BcuAxnp70T55r5T9ovZlvyLtJ2DpmuYXsa1F771cqP+t2GdgzT0l1wjC3pZUS8nKvlGGmyY8cvUPG3dNZ29FGzDPD9d7mXHsuHpuuh/e4lSL2VqOX64ts34aTV/z7+crKRx0/3FS8tAb9q8XI3hZmW4L/c9OzeUNQRgw/15CmjCyqm0vtKW1dPSpspF9RXL475BHrE6hz7HU9+wuo6v/4iWm25b2bj9ijMIsqoCjlSuwm988FGX/HS+klOXtH4WuEjTadOTYlmgZMqG+0KoSfKFg+Zj/TV/zwdNatFG0n2dTgOgGV9OAFWsnFY57y8q+otz6XnIs3w2KBVD9A/Le+M91ysIsnqKD+iVZ61uky7D5/uyvN2E1ZFy22CtEfoAzuo+41nmVOLRPmTZi7GSa8HO0/O3/gXFst+U0jhlLzJWtf4inQMwdnXrHJzhVrN/nEIvY+oZ3ip1y2tDy3799dfDuuR0CoXY1Vz6SJ89Mql93SncQrfwiB8ATC6dK3TO0HtOamFsyZIl4XGnn/70p6Exk9x5yPjH2dNHz4E69v5d+shdGeVLPYqqOoSnd5CscYgnnngivAtledge2/ONRyjf2m97Kt+rxWN7lzSXqqjlVM0j1ziF/QbVL37xi7DOeuxPdR+1Vpw7nvoRgRSuoJau7MVY+fnPfx67yv32t7+NXSM/6JZ7aVsHrp7P1QnJgg4FVgoM6lp/0bO1+/fv7wpK9Ly5Tl65Jo11MB47diyM4wMcBWQKsnppbaaKmvrUuvhn4G3b9MONbehZZTX/aVSg+JZ6dFL3+0E/0jveBi0AAOV0ztC5Q+cQVfRU+ZwzZ044n+n/sqb1/Qvzg1IxRP84ffp0+Oy1IS7P14tUT/N5+Msvv+xq8EH51tcDe6W6iS42aBm5FoxVt9E6qZ6meo+OJdWbBumH02fptlTsBiacvaQoOgE1DSoUiPlWtXSg9dLsJwAAADAZuCMFAAAAAC0RSAEAAABASwRSAAAAANASgRQAAAAAtERjEwAAAADQEnekAAAAAKAlAikAAAAAaIlACgAAAABaIpACAAAAgJYIpAAAAACgJQIpAAAAAGiJQAoAAAAAWiKQAgAAAICWCKQAAAAAoCUCKQAAAABoiUAKAAAAAFoikAIAAACAlgikAAAAAKAlAikAAAAAaIlACgAAAABaIpACAAAAgJYIpAAAAACgJQIpAAAAAGiJQKqPffXVV8WsWbO60l133RWHlvPj79ixI/Ydv48//rhr3vq/X2m7bT2b7LPJpOXbutR9H+l3vmfPnjhkzDfffNM1jpKmS6Xf19mzZ+OQ9qr2Z5vtAyaTjoMNGzYU119//WieXLJkSciXOm7KvPXWW135eM6cOcUDDzzQ12UcptaBAwdG80dZ8vnFl5l1iXJzuOncrPJG5Y7ygz5VjuXO60blmfJNWtapLOuV8nhaDtath/K81t2m0fpomrLyVv39+Oqumr+2SfPsZwRSfey9996LXWMOHTpUmekw2ObPn18sWLAg/jdSwKY++eST2DXmxIkTsWvM8ePHY1dRzJ49u1i4cGH8D5h5dKwsXry42LVrV/Htt98WK1euDOnUqVPFpk2biqVLl2bLTp30161bF8pWTa9pVIF4++23i2XLllHJRfDZZ5/Frol39dVXxy4MGwU+N998cyhvVO5Y+aNyTOVRrg6gYEQBj8q18+fPh2k0rso6lWUq09rSNPfcc09XOShV66F1VxmpdVe9RdOo7NU0P/3pT7PlrdZb42/evDmkw4cPh/nnAi/NX9v03HPPxT596jL6VidjXtZXlKbt27fHMfLajNvGsWPHuuat//uVttvWs3Nwx77TQ8u3dWnyfaxdu3Z0fOWB1Pr160eHW1K/lF+u5jkeVfuz7fYBE+3ixYuXZ8+eHfKgjgX9bzoVjcudE3U271q+1rRpebZ79+7RfN3PZR2mhpVz+/fvj33Gx8rxNE9iePhyS+WNZ/lDw315JjZM5ZrKN6Nyyua3b9++2LeelXVpOajlWn0kzadabm7dNY0dK+k0OnbUvxNAxT6Xw3qm8zCq/2gb+x2BVJ86c+ZMyFyW6irXnp9uIiu2OsD8vKlcNGOFStPvw1fglNJCNBdgq0BLWSGnNN58YBVOpbRwbLt9wESzk3FZ2aiTvuVRla3GjqWySodVWMZ7IQKDz/JPWh73wvKryuiJmB8Gk53r03OqsfIpDd4tL+bqYApSquaZY3WF3PyUP215Pq/acnJlo8azefry1uoRfjlW103XNzduv+LRvj71zjvvxK4i3PZ85pln4n9FuJXb5tn99BlWPXOqZ2HL5MZv+tytPberaWx6e2Y2d5vXP0euW76aXuPq1rZN698T0rr5Z3i1nrlbzul8PeuvJNo2v75126thfh1sGi0zd3u6rX/7t3+LXSO++OKL2DXy+JK+f+kUVKOPAX733Xdd+0Hd6mduu+222DXCvmPbz0pV3xPQ73Q8dE7q8b9uemRW5aj88MMP4VM0jSxfvjx8plavXh0+v//++/CJ4WRlq/LQ3LlzQ3evVL7ao1evv/76uOeHwXXhwoVwDr/33ntjn272blDZY6U33HBD7Bpz9913x65mVBdUXUF5+/bbb499xyh/dmKFkHxe1eN58vDDD4dPT+OpfiG+LpuTe+VA9ajnn38+PCqYW6e+E8Ip9B2L5pXslqducVo/XSktY+Mo+WnSlJuHXSnLpXRe6ZUCXVnw650mDUuv/Po7Hbr6Uja9xitbN03jb2+Ln296pcNPa1ecc8nffjZV4ytpH6VXGLV8G671asLvBz+Nv1ulK0F+ffyt8XRfeVXfsZKW7a8iSdX+7GX7gKlmebTNFU7L92mex3CxMlPlu/KCL59VDrfJU1Zmk6dQpeyujlj/tD4lVXeKcqyMa3vu1jRKad3L5O622bJyd6T8+to2lM273xBI9SF7jtSSZSZfidaBlFbYjZ+2LvlbxlpObpyy5A8GTetPLlXJFwp2YNUlzbtq/mnQ4+ebnrD8dHXJ72Ntr/XXCdW+lzQwSQs3Ld+GNS2s/DR+/VXYWH/lB59X/Hg+wPL9feGsT/sO0yBY03tV+9Ova9PtA6aSlZ3K403pWLFHa/xFCgyf9AKayjwlX2bmKrUpfw4ZlEoippbKHeUlK3vSc7FYnUP5z+pwms7XEdPgq4ydvzUf5Uktz/K11kH/+3qQ+HxcxsbRPIzVV3x9zbbFylirh+a2u18RSPUhX2irwm4sg1kqK7j9OEqq3NqBoMzqC38/f7sKkJtOy/LTKVklXPw6K2k5ZdP6irivoCv5AMUXCpb8wWYFjZKfp1RV/K2/JZun1jfdDr+NPohJ971flzSYsIIqN6yMX3/tO2P9lLQPtM6+n9F+tH5+mX6fpgWV3/Y2+7OX7QOmir9I0CZ/2vGgaa0sw3DSuVH5QHkizQu+bPTnixwrK9OyFxBfx6jLJwpKfL3Kks79TYMosTypuoHNT/38eV31G6uXSZtAKh3H6iY6puy40vztuNI+UD+/vH5HINWH/MFhlXzjM7e6c2y4Uu5A9AW/kvGV79x0duXAkj9p+P65yko6rR3o6bqkJyI/zN/6FR/4pfvCzzcdZv2VNA9PB68fXndiFBUAZYGL+O8st29yfCGkpP3l7z75qzx+/nZ1yv5XarINou/cpmmzP3vZPmAq+CAqzbdV/LHQ9PjB8LL8ovNAGeVFy1ODVEnE1FEdR+WUr0+oXxq8Ky/ZOCrfNI0/Dys/Nr3446fTPH3eVLctx5efvn5SpmwcrZcvX7V9tkybxuoR6bhaB6s79hMam+gzasjANxKQvgT9yCOPxK5mvyn1s5/9LHaNSRsesBdp1V6/yU136623xq5uacMXncweu8bYi4fGN6DgVb1YuGjRotg1YiJ+e+Pf//3fY9cIvZReRy9C6gVNNS6hRifmzZvXte8mQroftL/+z//5P/G/ouulev+iqsZJv4+yfarxtA3W6IR++wGYKVSu3XHHHaMvUr/xxhtxSDU1BGDHwr59+wbjZWdMqwcffDB8Vp0HrNEknR+bnGcwfFT/O3jwYHHy5MmiE1SExnDUqMOvfvWrOMZIYyUq15TXOkFG8eWXX4ZplDoBSSjrVH499NBDcYpmtCzNw+dNdVujEqpv+gateqWGKHbu3KnoKiRtsy1Tvxel9Xj00UfD/9oGbYu2sxNchd/L1Lb3W4NYBFJ95oMPPohdIxYsWNDVOpx+bM3L/Wivd80118Sucr4VK5Obrmnh3+SHX9VaTT/40Y9+FLvqWYuCCpz0w3X6MTwVLpPFB6T/7//9v/DDdcYHgD7YVqHnf4g3F9QqeFLgpB/S0zZoGh+8A4NOJ2cLonQSVgWhrnU0Hd+6MKITt07mqsikF4CAHN96WlllU3lS/MVQoIwu4KhVR9E52oKHvXv3hnJN53YFJL5cUx1NZZ3KL9VNqlpnTq1YsSJbRmqeVo+w+s5VV10VPptQHbYJravmb9uk40j/q/xWv40bN4b9oW3XPugnBFJ9RCdyi/6beuWVV2JX3ueffx67yv3kJz+JXWNy0zW9CtDkqsW1114buwaHXR0xuvKzefPmYv/+/aF7ot15552xa6Qg9Vc7ly5dGrtGCjorrHRF6t133w3d4uchCqIUPFngpOlUUOnKuz6BQbdly5ZwwUl5XMdnWtnIUZmlY0onbh0TR48e5U4UulSd1y5duhS78hchdfffylyCczS1atWq2FUUX3/9dfg8ffp0+EzP7UZlnYIiKWs23fvxj38cPtMnfqr4i+Wqt+ZYHdKacK/z5JNPhrLXjg8L2vyybH/YPugXBFJ95MiRI7GrOVWc00e5vPfffz92jfF3LMTuNPm7F6pIpMrufqUVDjsAPLsaZ3K/f9DPFET67dq9e3e4/b5169ZwcNdV1Hpx0003xa6R79noe0qX5x/18wGXn4f4wFvTnDt3LlQ0VXhdd911cQgwmHTHeNu2baFbFwd0fNZRBVl3r+yxmE8++aTRXXUMB+UPPQ1y8803l15M/Mc//hE+dScgdy6wc64vpwHdAdfTIVV1uF5onk2p7JOPPvoofFbxr1PYxWOVlzl24eGWW24Jn1X02KvK39deey32GXPjjTfGrv5FINVHXnzxxdg1kkntGdI0Xbx4MY414s0334xdV1LlX5ULu2qggEY/dGZ8wZ7eAfE/MJtOl/J3M3THQweGn9Z+gFAUCAxaRcWuBpk1a9bErpErMrngcbz8XScv9+N96bteJp2HD8jSH9Lzd7KAQaM7UW0fy1PFuO0jgBguOlcpT0nZxcSXXnopfJblOaukWqUVEN0NUtlTVoez9+qU/+yCtQUmZYGP6iN24Tq9kJpjrwaoDpO76+ovIvvXCOyu13//93+HT8+vw/333x8+y2jcZ555JtQL/UV5C9qaPFU17ToVc/SBTgV3tGUSpbS1vlQnABodt3OQdbXQ4udTl9RKitE8NK/ceLnkp9X6N53Wt7riW4NTSvlhaYtwftrOQRj7jqgaZv2V/DaY3PD0++lUukb7++9CKV1PLb9sWJ1OQN01b6WyVmvS8TRtaoFrpl3D9Z0r+f2l1GZ/jmf7gImg49TyYO6YLmN5N83TgGfln85x1jKqqOzUucCG+fOw10vexMzny620zuebN/fnVV/XUt7zeU7dVmfInf/LWB7WNL5+oWXZ/KzOY/x6+HXXOrQpV+3YSo8NrYf6q35lrOXitLXl6UYg1SeUEZVBLNU18Zg2J67/je9vB0Eu+WmMP3jTlM4rl/HLplXSMH8SEl9BV0r5YWkl3U+bHrBVw6y/Uu7EVjbcN7eeJh+gpMuzQkUp3YY66TK1D8ukAV2usLGCKJf8Nih5VftzPNsHTASfB+uSHdP6zA3PpTTPY/hYZVNJ50LlCTvf6bPsnK2KpU1XFmhhePm6nM7Bylf+XJwGMKJpfF1L0/gyUNPn8qMNT+s9PvhRsvzt/8/l3dy6+2NCwVYVDde4uW0UWwcNV91C82wy36lGINUnfJCiDNlEeiAZ66ekA0aZ3c9fFe70QPJ0APpKudZHmdifEJRy89A4GjfdHh0IuczvK+hKKT8sraT7af32S9Uw66+U24aq4ZqvtseGa97av1YgWPLbaoWBUroNdXxBpVRW4Eg6bhq0GvX334+6tV767vy2aX6man+OZ/uAiWD5r0myY9rn6bqU5nkMJ5WJvryrOrcZ5TcbH8hRHlGdywchdfU05TnlPX/O9ufyHBuvbL7K32V1gzK27jaNHRNV0xiNp2nKjh/NQxeEbb9oOXU3GabDLP3prCAAAAAAoCEamwAAAACAlgikAAAAAKAlAikAAAAAaIlACgAAAABaIpACAAAAgJYIpAAAAACgJQIpAAAAAGiJQAoAAAAAWiKQAgAAAICWCKQAAAAAoCUCKQAAAABoiUAKAAAAAFoikAIAAACAlgikAAAAAKAlAikAAAAAaIlACgAAAABaIpACAAAAgJYIpAAAAACgJQIpAAAAAGiJQAoAAAAAWiKQAgAAAICWCKQAAAAAoCUCKQAAAABoiUAKAAAAAFoikBoAO3bsKGbNmtU4jdddd901Oi8t23z88ccTupzx6rf1KePXsWny+70X/jtUNzAMvvrqq2LDhg3F9ddfP5r/lyxZEo6nb775Jo51pbfeeqvrmJkzZ07xwAMPhDIGkAMHDozmj7Lk80ub8/Z4y3sMtrNnz4byRuWO8oM+VY6pPCuj8kz5Ji3rVJb1Snk8LQfr1kN5Xutu02h9NE1Zeav+fnx1V81f26R59jMCKQDAwFNlZPHixcWuXbuKb7/9tli5cmVIp06dKjZt2lQsXbo0e8LWSX/dunXFoUOHwvSaRhWIt99+u1i2bBmVXASfffZZ7Jp4V199dezCsFHgc/PNN4fyRuWOlT8qx1QeqVxLKRhRwKNy7fz582EajauyTmWZyrS2NM0999zTVQ5K1Xpo3VVGat0XLFgQplHZq2l++tOfZstbrbfG37x5c0iHDx8O888FXpq/tum5556LffrUZfS97du3X9ZX1TSNV+dgGJ2Xlm2OHTs2ocsZr35bnzJ+HZsmv9974b9DdQMz2cWLFy/Pnj075Pf169eH/02nonG5c6LOHgtWtmpalSfe7t27R4+hdBiGj5Wp+/fvj33GR/k0lycxPHy5pfLGs/yh4b48Exumck3lm1E5ZfPbt29f7FvPyrq0HNRy165dG4al+VTLza27prFjJZ1Gx476dwKo2OdyWM90HqYTnIVt7HcEUgPAB1JTUejaQaDUz4HUIPP7cTIqaf47nIo8A0wnOxnrxJujk74dD2fOnIl9R07U6ldW6bAKiyoTGG6Wf9JKbS8sv+YqyRgeFsCUnaOtfEqDd8uLubqDgpSqeeZYQJSbn/KnLc/nVVtOrmzUeDZPX95aXdYvR8PVL13f3Lj9ikf7hkD6/L9Sk/cGeqH5ab6avy3Lnpktew7Wr5eet9X6+unVrWd3U3XvSOXWRUn7QstI+flpHJveP4M8le9N1G1f3XBP+17fgR4Z0LjapqpHlrTtGt9vu/bJnj174hhAf+mcuIvOST3+123+/Pnh8RH54YcfwqdoGlm+fHn4TK1evTp8fv/99+ETw8kea1Iemjt3bujulZXF8vrrr497fhhcFy5cCI/E3XvvvbFPN3s3qOyx0htuuCF2jbn77rtjVzOqW3333Xchb99+++2x7xjlz06sEJLPq3o8Tx5++OHw6Wk81ZXknXfeCZ9lFi5cGLvGqP7x/PPPh0cFc+vUd0I4hb42njtSdkW1LOm2aXpFTMuw4W3uSOnKgl2FyCUNy1359eNoffz/PqW3fqvWR9tUNS8l7RvPz0/TVk0/3sc7/LzKrrjU7e+q4f471FWtsu8l9/3XfY+5aYB+Z/m37HjLsbK3bbmLmcXuIKnsU17w5aOuyLfJU3ZOJk+hStldHbH+ufpU1Z2iHCvjfF2vCU2j5B8t9HJ322xZ/nixO1J+fW0byubdbwikBoBlvjRT1vEVbZ0ALFPaScFSejBqGTbMH1xVFXf/vGxdSguF3DhlyR+AVevj95lOXFbxTwNLf6Cm86tK2p/j4eflt8mr2j6pGu6/w7rkn1f2hXdValpIA/3ATurK203pWLBHa3LP72N4pOcNla9KvqzMVWpTvswelEoippbKHeUlK3vSC75idTjlP7uoq+msnFNK61llrK6g+ShPanmWr7UOvv5kfD4uY+NoHqbJO1JaB/2f2+5+Vb4X0Dd8UFCXPFV2rX9ayNtBquSDJeklkEpPNDoo7ODTsv0JR/P3/HRK/sD1BYOSr8BXrY9fnj9h2UFqSfMw6fw0Dxuu6RQ8+eHj4efj18Gr2j6pGu6/QyXtN9sPms5//0q5/Z0W0mk+9PsV6Ff+Dmta1lWxMk3TphUJDBdV/JQPcpVKXy6WleXGyuVBqiRi6vg6W10+0bnZyjWfVE9pGkSJ5Umd+21+6ufrEKov+PO9r3uUKRvH6lE6puy40vztuNI+UL9Bql+MrzaIKZFWYKtSE8qwPihIKxf+APLDqiruvn+usmJXHSz5A93317JT6fabqvUpo4PTT+NPfOn8LIgw6TaMh5+PXwevbvuqhqeFYCqd1tah7Ls3Pt/YFSSgX/kgKle2lLEgSqns+ASM5ReVj2WUFy1PcREKOQoiVE7586z6pcG78pKNo/JN0/hzdy7gL+On0zx93lS3LceXn77+UKZsHK2XL1/Ti7zqZ3WPdFytQ5sgcaqMrzaIKZEGElUpR5lRQYHm4w8aS2mF2Y/jh/kDQ8mk/csyuh/H3yHz/dN1kbL5l62PpwNUy9KVD184WdI8TDq/tCBqsrym/Hz8Onh1y6sa7r9DFUQ5floLiny/upT7roB+oXLCgigd+00rFv7E7cspoIwvi8tYvvIVUqCM8pSVXwo2jOo01l95ypdrZYFPFasraJ65MlLz1HClXN2rTJNxUloXvx62btpO1Tc0TMkCr35Bq30DppOxlCtLk2ctr82bNy/80Jp+vE0/tjbZcq2wpNRaTa98q1tl1MqSWplbsGBB+IG6bdu2hR92a2OmtKZ03XXXxa5yly5dil3Nffrpp7EL6C9qlfOOO+4IrVF1TsLFwYMHa49nlZcqM/Rjkp2TddGpCIy2PAVU8a2n5X64VKyl2EceeSR8AlXUWp1adRS1kGetHu/duzeUa6oL7ty5s6tcU+ukKutUfqmul2vtuMyKFSuyZaTmqWWJ1R+vuuqq8NmE6mBNaF01f9smHUf6X+W3+m3cuDHsD2279kE/IZCawR566KFQKTCLFy8OvyS9f//+0aaAJ0PZicS79tprY1d7dQexKkSqRPmgUQXB9u3bQ+Vopvj8889jV7UmAU/u+1A+yQXrlnJNyAPTbcuWLeHiiU64Ku/SykaOyqylS5eGMkMn/qNHjw5Gs7uYMlXnNX8h6pprroldY/RTFcqPQnCOplatWhW7iuLrr78On6dPnw6fd955Z/hMqaxTUCRlzaZ7P/7xj8PnokWLwmcT/mK56ls5Vj+xJtzrPPnkk6HstePD6m9+WbY/bB/0CwKpGUpXL3wgsXv37uLkyZPF1q1bQ2asq1i0kVY4/HJNWunO/f6BvPvuu7FrzPHjx2PXiLo7XkeOHBk9acmZM2fCVRpd0RjkylH6O1xNAlY5fPjwFYVd+ltYdvL3AfaHH34Yu4DBoDvwuvss+/btC+VdHR1HuvBy/vz5kP8/+eSTRnfVMRyUP/Q7ejfffPMVZbD5xz/+ET51JyB3brVz2NqS3znDcNIdcP2240T/NqXm2ZTKPvnoo4/CZ5Wrr746do3VFVRe5lj95JZbbgmfVfT7lCp/X3vttdhnzI033hi7+heB1AxlVy/MmjVrYtfIFYRcsDMeuv1q9AihDgyrvCuIsh8gFN0dKquo6PE7jWsnLE2rH2YzTU5E/rFBHex+WW1udfebF154IexTJe1ff7exioJKFdi2T1VoP/XUU6FbdPK3APO+++4Ln6L5++9R3fbjvEpNAzlgKuhOVNvH8nRMtH0EEMNF5w/lKXnvvffCZ+qll14Kn2V5ziqpVmkFRHeDVPa8+eabsU83nXPFn6MtMCkLfHS+tgvXN910U/isYj9Grjph7pyuMtLqi/6Hy+2u13//93+HT8+vw/333x8+y2jcZ555JtQL/YVuC9qaPnkzrS6j7+klO31VSp3MFvtW8y8IKullPeuvFxf9sLTRAC0jN8y/PKjkab6dg71reFlKG6PIjVOWtA6mbH3S1vXshXGN3wmsuoY1mZ+pG96Gn49fh1TTfark+e+wLvnvWC95Nllm03wITAV/bFYdTyk7TsjPqGLnYJWNvjVXlZc6t9qw3Mv60kvexMzny620FVzlMzsX+3O0r2sp7/k8p26r4+izKcvDmsbXz7Qsm5/VIY1fD7/uWoc25aodW+mxofVQf9/QhvaJ+qnxsH4yvtogpoRltKYZ0yiz2XRpUpPY1p3O0w4CJX8A+4NeKaWMbwdWLmmYPwkZP44O2rJ5pC1oVa2PHfy55Le9zfbVDW/DzyctQDz/3afJCj9Lnv8Oq/ZFWjhK3feo+ZVVGIDp4PN7XbLjLT2eq1Kbchczky9vVQYqT1g5qc/0AqFRWWnTUW4i5S/8qm6ifOXrKLlztKbx52hN48tATZ/LjzY8rXP44EfJ8rf/P5d3c+vujwkFW1U0XOPmtlFsHTRcdSHNs8l8p9r4aoOYEr0GUqJp/UGp6ZX5LQNb8hnTH0BtAg3RwaZpfOVdy9eBUJb5/Tw1rQoAf9dM88oFYFXro/XQMv1BrXlqmvTgN3Xb12T7m/Lz0XyraH39/rTvUPx8vPQ71DLSfWrzyNF3pf3n846m0byoDKDfWB5tkux4U17ODc+ltuUuZiaVmb5srTu3iT9vADl2fs7VV8r0co628crmm9Y1mpzzbd1tGjsmmtQTNJ6mKTt+NA/dELD9ouWUXbCYTrP0p7OCwLTR+zamc9CGRiEAAACAfkZjEwAAAADQEoEUAAAAALREIAUAAAAALRFIAQAAAEBLNDYBAAAAAC1xRwoAAAAAWiKQAgAAAICWCKQAAAAAoCUCKQAAAABoiUAKAAAAAFoikAIAAACAlgikAAAAAKAlAikAAAAAaIlACgAAAABaIpACAAAAgJYIpAAAAACgJQIpAAAAAGiJQAoAAAAAWiKQAgAAAICWCKQAAAAAoCUCKQAAAABoiUAKAAAAAFoikAIAAACAlgYykLrrrruKWbNmVaY5c+aE8fbs2ROnmjjffPNNsWPHjuLjjz+OfdCG//60H6eDlmvroPVpyqapStdff33xwAMPFAcOHIhTTa9+2N+DSMe3/1453gEAgDdj70h99913xaFDh4onnniiWLJkSew7fqocL126tNi0aVPsA3Q7f/588fbbbxf33HNPsWXLltgXAAAAM8lQPNp36tSpCbsSr8qxKspAE9u2beNOBgAAwAw08IHU9u3bi8uXL1+R9u3bV8yePTuOVRSvvPJK7MJ0O3jw4Oj3tHHjxth38Bw7dqwrzyldvHgx5EnvzTffjF3TY6bsbwAAgH4yY+9I6R0VJVN2F0mP6vl3SPR+y4YNG4qzZ8/GMUbYON6yZctCP3vHJn3v5q233grzs/nqf093KrSOep8rna6K3tHSI2M2b5u/1vurr76KY3XTNBrup9Gyyt4hs+1V0nZpebaeelRSyYZrvjnattw46bxTvWyf+qfbp/XVOkzlHaG5c+eGYGXBggWxz8i65Wjb/X5Ut7Zb219G+dVPo+1TXk3f5/Hq9rcoz/nx6vadz+vqtv1veUSfVd9XlXRdlLTNWk5u3/hxtb52XFk/5YmyaSUdX8uqOwYBAAB0lXrgrFy58rJWXWn79u2x75XWr18/Ol5uU9Phadq3b18cs3uZadIw0bpYv05FumscJT+/umVrnhcvXoxjjzlz5szl2bNnZ6dR0jCN49VNs3jx4iuW5bc3ty27d+8e7da80+n1vx/fr1PV9zcZ26fk973478q+vyb8PI8dOxb7Xsnvs3T+2jfa535ePuW2UcryjMb334eSV7W/69ZFafPmzXHsMX7/rV27tnT/q//58+fjVPXqjou6vFo1vaZNKV/kxlVK90vV9w0AAIbPjAykVNFKK0iq7Hm+IliVrELrl5kmqyhXzVMVa6OKaW6cNKXrrO2qCxiU/LKaTpMuq2p7VVkVHyykgYrf/359pOz762X7xM9PAYVoXr4inE7jvyv7/pqwaZRyFWsFDen3a+tkqvatJa2vtsHs378/O15Z8sr2t9QFUZbSbWh6/CjlArEc7U+bRutlAVh6LKd5rcn+tKT9aDT/3DhliUAKAAB4A/9on1rPs0dyLM2bN69Yt25dHGPEr3/969g14vnnn49dRdEJDMKjf539Ed576VTi4pBi9NE3e8/E07jqp2E5mo/N99y5c6GfHnVSAwRG43SCtTCOxu0ENHFIEVp+849W7d27N7RGaDqV2zBdp8IdtsFoPvZo0nvvvTc6TSdIKToVydFpOpXh0F+0rKrHsDR/TaNpd+7cGfr5df3ggw9i14gXX3wxdhXFb3/729hVrZft02Ntap1ROsFH8fjjj4duPWL3m9/8JnSLpplo9minT1oH//1qn69Zsyb+172+om20/doJEEbf69P6HjlyJHTLH/7wh9g1Mk+Nm9s3bWgfqiEWU3UcPPPMM5WPHPq8rmltO+T06dOxq9rLL78cu4rw3c2fPz9067E77Vdz4cKF2JXn86r2r/fZZ5/FrpH85ul4yH0XAAAAWZ1Kw8BpcwW6Uxm64gq2riz7cVL+6r+m9/x0mo+XXqX3V7+NH0fz7lTc4pAxuhth4/g7RX67O5XF2HdMpzIb+vvlVt2NEE1jw/1dh3Qf59azU3HOjpP21/9e2Tr1sn1V9L3b/JQ8/z1ouU35+dUlfY/pI3p1y/V3s+y71361fkppfpb0+/Ka7O/cuqTfo88ffjuU0vyh78mG5ebdhubt86nfBvHbofFS/njy0/p55vJbmn/S4x0AAAy3GdvYhK4m66ryl19+Ga5oe8ePH49dI9K7Cmri3Pg7JG2tWrUqdo356KOPYldRrFixItw5ST322GOxa6TpduPvZKxevTp2jTl58mS4W+SX66fJ3b3z87906VLs6tapqGbXU3cMOpXR+F8xegfF30nRtHZnoU4v2+fpbo/uIFqjE+ldyamifaI7f7oLuXDhwth3hP/+tb3p9+HvZn3//ffh84svvgif5tZbb41dY+68887Y1Zzf3/fee2/sGqPvTd+fSRtgMdreNH9cd911sas93flSoxpqIEINSegOs8+nVXRMpZQXcvw8f/azn8WuMbn9DAAAYGZM8+cXL17seoxHAZB/vGw8yiqQ47Vo0aLYVU6PS+X86Ec/il0T59NPP41dzfnH5+zxvldffTV8yiOPPBK72mmzfap0q7J88803hx9g3rVr16Q8ypfSI2zKe1rWevd4nSroH374YfyvdydOnIhd3ZoGpm3ceOONsatc2aOfuSC7FwqgFAQrcNLFDAX+Pthr4uqrr45d7VxzzTWxa8xk7GcAADBzzJg7UqrM6f0YH0ypQqsr2lV0NV2V4aqU3lWYKE0CF/9uiPevf/0rdjWnuyS57bPUS5PPy5cvH32XRO9ZKei0K/3qr+G9aLp9eofM/0iylql3t5QPfF6YTKpw606Zf2dMwZyaMq+yefPm7Pdg6dtvv41jduulSfE6n3/+eewqN9mBxUMPPRT2m9GxqX2kfOvvfE6G3PZPxn4GAAAzx4x7tE/BlH8cSZV6PSLk3XTTTbFrZPhUVpj8I1iHDx/OvsDvfzzYVyD9dv3P//xP7Bqjq/l6jFEBkc3XTz8Rd0lSCmD9o5O//OUvY9dIIwFt7lb0sn3+x24VdOpRTg1XPmhyl2Ui/eUvf+lqoECP6fnGQuSWW26JXSOBZxM33HBD7BqRu1PlHxlsyu/v999/P3aN0XHh7whN1gUFSZelIFiPcm7dujU8yjlRd708v/1Hjx6NXWPUUAsAAECZGfmO1BtvvNFVodUjQv7xvKVLl3YN150EG64KXfqDp2XsKnabR/98C256/FB3zPyytTz/WJpvbdAHYbpyr/eBLKBQt/qpcq53g37/+9+H/vfdd1/4lNw0/v2cNtvhPfjgg7Gr+70T37+JXrbPB8H6Hn2F++9//3vsmhpa9t/+9rf43wg92mjbIHfffXfsGnls0/9orYIu+0FbJW2zaL4+INY0dvdQ0+r/to/AiX/sUtOn6+LvsOl48Xl3on399dexa4RflvZfL9tXx+c35Sv/o73av75lTwAAgCtcHkArS1oh83bv7v6B0k5FNA4ZkbY6VpbSlrpy42h9JJ1nmfR3hspSpyIbpxih1ss6FdrsuGnqVNJbTWPbYPw+Tofl+JbRlPR/mbLvr5ft863DaVprJU8trqXz8vx31WT7jJ9fWStu+t78eOnvKPntL0tad+0Po5YKc+OVJa9sf4uOCz9dWdLx5NXtv7b7V9+nja9kreipf7o/022o2j4pG94mvynRah8AAPBmbKt9uUf87Aq/bNy4sfb3d9Tq3+233x7/G+Gv0ht/x6EJPa5Ut2wtR4+KebozoUeQOpW/2CdP623vszSZRnc7dBdvPHxLg5L+30Qv2/f000+Pjq87fGpwQndzrMU+P6/0MbvJknvEz9/t0772d5hSmlb7QfvD6PG2sjyj8f2wsvfqcvQbaFXrIp3gY/T3uSaLvk+9D2V091Hfo7ZFd4v8NvXyGGOO9u/rr7/e9V15dfsFAAAMtxkbSIkaAPCVJP2oqH8UTMNVKfcBl8ZXEKMW2XKP9amSrEqrzVcVPD0K2JaWrWVoWX4dtS5aJz1a5CvSRu+p6D0gVTp95VLdWi/9uG+63ppGgaSG+2lUUVQlWZXp3LLaSB/76vUxsLbbpwq4gg4f4Nq42mY/rn+fajJZBd3z745puPa59r2vrPv1zr2PZPnVT6Pxtb98c+NlzX3naF30LlLVcaCLDlNBFxi0T/z3bseD3ic0eszPH8fjoQA1l3/suAAAACgzS7elYjeAAaX3e/QuoCj4IAgAAACYXDP6jhQwU6hREmuEQsk/pqhu3zDCZDdTDgAAAAIpYCCkwdGyZctGgyp16/0w07a1RAAAALRHIAUMAN+oRhW9M5U2kAIAAICJRyAFDADdkVKjEmoEwTcKIdYwhBplUIMUwLCy31VTgyt2x1aNAfnfCMtR4z7+8Vn9npsaqpmqlj7RP3rJQ+qv4f43KDW9/22+HOUv5TObRvmubhoMl7RsUr6qK8+qaLpc/rbfpsxRq8PKp/Y7l03yqeZny9CnbzU7deDAgTBe1Tr0tdAIOgAAA0y/ITc7/i6YPleuXNn1G2ILFiwY/f05b737LbrFixeHaTSu9due+W0yzEy95CH9Hp3yjY1j0/j56HcAU/v27euabzqN/SYihpcvm9I8ov/b5pFc/vZ5V8tL5fKpPm0euXWw373UvFV+ahr9X1aWan5Kg4pACgAw0PyPK6sy4H/MWhVfqyzohO7pxG4VgvQHl/2PuvNjzDNfr3nIKoka7oMsTW8VYc03nZ/6K/kfO/fTDHLFEuNnZVOaR8TyiPJcU8pbFgCl+Vvlmy3Ll3Uax46JsnVI87bYseL7a9kaN2WBWu5iw6AgkAIADDQ7GZdVPn3F1V9BtYqFps+xysLatWtjH8xUveQh388HUZ7lMV8RtUpyGpSJKp82TwL44WUBTNldHAvgy8qulF0YyuU52bx5cxiuT1M3jeXtNAjKTaMyVP1zgVrZ/AcF70gBAAZe54Tc9cPKnt4xXBx/yPqHH34In6JpZPny5eEztXr16vD5/fffh0/MbG3zkD47lcnQv+xnJ2x+ly5dCp/eLbfcErvG6EfSOxXL+B+Gkd5JspZ4H3300fCZeuSRR8LnBx98ED7rvPrqq+HzySefDJ8p/SB+JyYIn+bChQshf997772xTze9+ySfffZZ+KyyaNGi2DVm7969YTufffbZ2GcwEUgBAAaaXoT+9ttvuyoBqVOnTsWuMSdPngyVB1Vec5pUEDAz9JKHFi5cWJw7dy7kozKnT5+OXWOuvvrq8Pn222+HT0+NARw6dCh0X3XVVeETw8Vf7Ckrm6655prwmSvXcmy8VatWhc8mdCwofz/++OOxzxjl0xMnToTuJoH/p59+Gj4tT6uhCv3+5foZ0NIwgRQAYEazFqN0x6HpSVsVhVdeeSV0l12RxfDoJQ/pzoIFRb6yuWbNmnAX6/z5812tn2l8tdAmupOlQA3I+de//hU+lYfqWOujdkdVreP5FiaV59RyXhMqFzX90qVLw90kBUJpPtVylO81rlEgp2PHxn3hhRfC9Pppl4EXHvADAGAG8i1Vlb1vkFP1MjWGSy95SHmmU6HMvi8iGm7vjaSpTT7FzGT5rewdKOUpyy91rDEJTWPlmt5v0v/2npNSXb5L86vmlVPWap+9J6jjSf/797EGGYEUAGBG8hXgXGW2jFU2lHjhf7j1kod8EFUWiKuCaXlM4/pKrT4HuRUzjJ/lD+WftAzyeUepjgVSltIW+KxRCaWq8k6BlPKp5W0l9cvlb+Vfn5/9MjUPf1z4cdW/LqDrNwRSAIAZx1eAdeLPnexzfBDVtEUszEy95CGN44MozSNlLaRpeFpxbVqpxcyngMPyggXblh+tlUmlOj6QKgtSrNxTYNSE5mnr0nQasXWx9bD/FUipn931GqS7VQRSAIAZRZUMO8mrgtC0AmwVl1wFF8OllzykoMmurKvim2sSXfPRcKWyPGZ3HDQPDDflBQvMlRRoKN9Y0/vKo3UsWFHKBfbix2nKHuFTKmv+P6Vt0TFiLHDy09v2Njnm+gGBFABgxrCr/UpNr2r6CrA+yyobGA695CEfeCkgL6sENqmwKv/VjYPhZkGM8lqdJvmpl0BKbBpNX8fuounT6P80GLQLCU3m2Q9otQ8AMCOoBbRt27aF7s7JurIpa6OW0u64447Q+tXixYuLTz75hNbShlgveUitmK1bt260FbODBw+WNlvdBM2eo86HH34YPnO/RZZSedYJVkK3teBXxsYTteY3Z86c2mmaUAt++r2oTuAXfmrAu/XWW2PXYCKQAgAMvC1bthS7du0KFYFjx45dcbLOUbPTCqImqgKMwdZLHlKz0QqiZPfu3cXOnTtDd5kbbrghdpVXat97773wqcAew0lBjJomz+URlVsK3uX+++8Pn3UsL7/88svhM/Xmm2+GT5/nf/zjH4ey0Yal2vwkgH58Vxer0h/f1bT2e1QDK96ZAgBgIPnHUto8DmLvRDV5PAYzWy95SI/vdSqCYRp7eb4Je3RQ06bLsseflGi5b3j59+T8Y6J6l8jeIdK7e01pOstXaV71DZz4d5X8MeFb3RPlzaZ5346TXDlr70j5x6l5RwoAgClkAVGTZBVXX0moSwRaM18vecgqu02Sr2yqguiXp/fy9L+9p6fU9N0szEzKIxZQKCl/+DyTBljGxskFNwrSLfixwMbnOf/ukvGBfS6fNgnmNI7G9UGasXJY89Q602ofAABTzE7qTVIvlWBVHjCz5b73smR5yFds61JZxdbPQ5Vba5UNUKCkfOMDFwVQuYDHWH7K5TdRMKPAxgdUdXlOwzROm2mM3QmrCrg0HwsaLaAaJLP0p7PyAAAAAICGaGwCAAAAAFoikAIAAACAlgikHDU1aamq3XxrllJpx44dsW83NU/ZpOlUTC99f/Zd6nttyqZRavMbC70uD9U43gAAwFQjkJoEqiwvXry4ePvtt2MfAJOF4w0AAEwHAqkJprsTmzZtCj9iBmBycbwBAIDpQiAFTKGNGzfqJwdCOnjwYOwLAACAQUMgNYH03suyZcvifyPsfZj0XaoDBw50vWt1/fXXFxs2bCjOnj0bxxiTvlfz1ltvhfFtOv3v6Sq93heZM2fOFdOV0TsmWr7N15Lmo3Utk1uWbYvmWUbbqXH8dEuWLAnb+s0338SxRrTZ/tx2aBlaxzbvMk2WdFtyNI6tv9Zd26N9Ujet9oP62zhKZftU+8KPJ+lyt2zZMjqd7VcbX/Otyhdt8rdfF01j2+q/w9z3p/5NjzcAAIAJp9+RwgjtDktVPzTmf0DP/3CYnz5Nfjz7leeylP7Ymqa1Yf6H2Sz58evmrXVPfw37zJkzoz+0VpZyvzLtf/E6lzRPzTtVN136i91Nt7/JdlTtW+2bpvw8m/wonalaXvpL5j6pv74D+z+dtu57T/ep1jkd7v+3pOVU7df9+/fHOY5pm7/9umg9ytZFyS8vN9ySP94AAAAmA3ekppiulO/atSv+l7du3brslXs5f/587BrRCSzC1XrRHYS6eR86dKj41a9+Ff8b8ac//Wn0HZPdu3ePPnqmbrNt27auOwK6a6A7DNKpZBedynCYplPpDv+L5rlnz57QbTQPbV+VU6dOFb///e/jf92qtt+/K2Pb0QkeQkME5tlnn41d/efPf/5z2PYc9dd3kKN9at+7tlX7SNveCVhCP9H0R44cif9dqWy5yi+/+MUvSt9B+sMf/hC7Row3f2s9ytZF0uUBAABMFwKpCaTKqwIKT/2U9G6MPP/88+FT1q9fP1rp1XS+wp8GIJ6vLJ87dy7006NXvqKtcRTUaByNu3bt2jikCK2b+aDIt3b2b//2b7GrKB5//PGu6d58883YVRTvvffeaOVagcztt98euhcuXDga2Ej6eN9zzz0Xu7oDMK2j335VxsseDcxtvyrmqvSLgiutu8ydO7f4zW9+E7pF0/UjBabp91e2b1Ivv/xy7CrCts6fPz9063vQvjAXLlyIXVdKg2FPy1deVVCq5PNEGvRMRP6uyhd+eTZfT/2U7HgDAACYLARSU0jBi7+yv3PnztFKrwKRP/7xj6Fbqt5n0ng2nVFgY1QRVUMGCmpE42p+vlLtK992B0luvvnm8P6LKroKTjSdVU61vkaBSq5/HQt2RNNZAKZ1fPXVV0OlefPmzaEyn26jyW2/ttXWx4KrQfLJJ5/ErhEKbv2+0ffpvyfPf0c+iFVwVjZN6ne/+11XMLxy5crQLZqHvisFpUoPP/xwHNJtovL366+/3rXtPhAGAADoFwRSU+j48eOxa4S9GG/pnnvuiUNGHosrs2rVqtg15qOPPopdRbFixYpQ4U099thjsav7yr6vfIuGPfHEEyGossYOyu4OiSrQeqRL89H4ZY92+btgsnz58tg1QhX4kydPFlu3bh0NAnNy2+8pAFQgqPVWgwV1jxL2g88++yx2jdxRSwNFfZ+33npr/C9PgZMaedB3oUYb5s2bV/mYnHfbbbfFriuly/3Rj34Uu7pNVP5eunRp7BpxzTXXxC4AAID+QSDVx8reI6mzaNGi2FXOP+L2v/7X/+p6XMtThVeBkSr36V0EVdgVOKnlNL2fpLsoVRXkVC7YGw8FEQqcFAAqENR6++0cFNqGNux9NQVOClb0Xfg7f/2qLH9PdL4AAACYDARSjn8M6vPPP49dV1LFdbz0CJs9jlWWqu7KVPn0009jVzn/mJ8qrgqS9DidHqvzwzxrXEIURPnGHTSN3olRAwf6bKLqLldbutulIMICJ32XCg7V6IRvNGMQtH008aGHHuq6C2iPR+7fv7/r/aKpNJn5GwAAoB8QSDn+Eab3338/dnVT5d8/LnXttdfGrno33XRT7Bp5fG4iA4k777wzdhXF4cOHs8HeK6+8ErtGKropVWz1WJ0q8gpIFBT5d2UUNNnjeX5eClg0jd6J0eN91113XRzSzd57MSdOnIhdY/R+lgK2qt8oyvENYSio+/LLL0NwqHe5brzxxjikf/m8oX2f5g19n7n9pfH83ScFjfZ4pB6BnMq7O5OZvwEAAPoNgZRzyy23xK6RRhEUFPjHj1S5Tx+Bq3tvRdOrEqxKpd798He9NC+bv4YriLD3SdL3luqsWbMmdo0EPHpHxs9b8/OPuf36178On9om/x6LBWB6R0fTpM2F/+QnPwmffl5p4wPvvvtu7LqSD8x8wKTl6n9VwHV3RXeXqhokSPlKu/arDyD+/ve/x67+lb4XpG2woFXfo77P3GOTX3/9dewa4fOB9ulUPuI3mfm7KX+8AQAATCYCKefRRx/tqgjqnR+9b2OVP1Xu/d0oBQVpowApTa93V9Sqnir3ah3NaF42f91F8fO2QKcprYce5zLpvH0T56rg2t0h3bXwd6f0G1NWCVWF1N/p8dvrH//Tb/toXCU98ue3I+UDMwUG2qdaR+0j/3ia5t+msu2/B83HKvAKxvx8J4PeEbM8UpbqKG+k35/NV99j2T61wNbY72/pO0x/L2yyTWb+bsofbwAAAJOJQMpRZfzo0aNdwVQZBR9vvPFG/G+MApTc9JcuXQqf+n2buneI9Ehd+hhcE3qcq27eCqL+8pe/xP9GKMiyYErdqvSq8uuDG/XzzZy/9NJLsWukwqxxlfTelA+y0jsi2i7/Q7E52n9//etf43/NPP3006P7XQGaVeCtxT7/naStB/aL//zP/8w+cinq7+/mWeCYBtD6vixwse/S+JYdJ8tk5u+cuuMNAABgshBIJfSekN6v2b59e1fFVVRhUz9VBPUeStn7JwrGFLAYVYL9u1QKSNL3jzRvTaMfGB3PY0+at+ahefkKpq237tCk663KuH6nSO/XpNusdde+0O8c+bs+upOVNmbgx/UV+PQRPW2fGrZQhduvo6ZXUKD937YhAguC/X7XOmgZCvT8PvV32fqJvhd9D9qHtv+0f/S/8pvn30NTAO2nEfu+9b6cUVA7FY+8TWb+zqk73gAAACbDrMtqPgtA39N7UnaHT4GT7v4AAABgenBHCugTeiTPkn5Lyt890g8M+8ckueMCAAAwvbgjBfQJBU++NcQyekxOjz+WPVoKAACAyccdKaBP+AY8qugdJIIoAACA6cUdKaCP6HG+F154ITQu4ZsLV0MSK1asKB588MEJa/EOAAAAvSOQAgAAAICWeLQPAAAAAFoikAIAAACAlgikAAAAAKAlAikAAAAAaIlACgAAAABaIpACAAAAgJYIpAAAAACgJQIpAAAAAGiJQAoAAAAAWiKQAgAAAICWCKQAAAAAoCUCKQAAAABoiUAKAAAAAFqadblj1qxZ8V8AAAAAQB3uSAEAAABAS+GOVOwGAAAAADTAHSkAAAAAaIlACgAAAABaIpACAAAAgFaK4v8P8HuXFdYTHn8AAAAASUVORK5CYII=\" style=\"width: 586px; height: 322.645px;\" width=\"586\" height=\"322.645\"\u003e\u003c/p\u003e\n\u003cp\u003ePercentages are calculated based on available data.\u003c/p\u003e\n\u003cp\u003eAccording to the available surgical descriptions, 74 (48.05%) capsule resections, 40 (25.81%) oophorectomies, 37 (23.87%) cyst drains, and 13 (8.44%) cauterizations were performed.\u003c/p\u003e\n\u003cp\u003eWe obtained the description of the pelvic endometriosis stage according to the American Society for Reproductive Medicine (ASRM) classification for 248 patients, distributed as follows: 21 (8.47%) cases of minimal endometriosis, 26 (10.48%) cases of mild endometriosis, 90 (36.29%) cases of moderate endometriosis, 103 (41.53%) cases of severe endometriosis, and 8 patients with a diagnosis of abdominal wall endometriosis (3.23%). Thus, 77.82% of the cases were in stages III or IV and 18.95% of the cases were in stages I or II.\u003c/p\u003e\n\u003cp\u003eAll patients included received drug treatment according to Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e below. These methods were studied according to composition, isolated progestins (P) or combinations of estrogens and progestins (EP) to facilitate data interpretation.\u003c/p\u003e\n\u003ctable border=\"1\" id=\"Tab4\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMedications prescribed at the start of the follow-up.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMedication\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFrequency\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePercentage\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTransdermal EP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.30%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eOral EP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e137\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e41.52%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eVaginal EP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.21%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eGnRH Analogs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.21%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eIUD P\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.55%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eInjectable P\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22.12%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSubcutaneous P\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.30%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eOral P\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28.79%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e330\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eEP combined hormonal contraceptives, P progestins.\u003c/p\u003e\n\u003cp\u003eTherefore, 4 patients (1.21%) received GnRH analogs as the first option of medical treatment, 142 patients (43.03%) received combined methods prescriptions, and 184 patients (55.76%) received a prescription for isolated progestins. The preferred prescription form was continuous.\u003c/p\u003e\n\u003cp\u003eAmong the combined contraceptives, the most frequently prescribed dose was 30 micrograms of ethinylestradiol, prescribed for 95 patients (28.78%). Among the isolated progestins, the most frequent was desogestrel, prescribed for 87 (26.36%) patients. As shown in Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e, the median treatment time was 18 months, ranging from 1 to 168 months. Of the total, 177 patients (53.63%) discontinued the proposed treatment.\u003c/p\u003e\n\u003cp\u003eDuring de follow-up after starting treatment, the patients reported several complaints, as shown in tabre 5.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ctable border=\"1\" id=\"Tab5\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eSymptoms reported in follow-up consultations after starting the first proposed treatment.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSymptoms\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFrequency\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePercentage\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHeadache\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.33%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePersistence of Pain\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33.33%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSpotting\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e164\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e47.9%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntense Bleeding\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.24%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eBreast Pain\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.91%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNausea\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.12%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eWeight Gain\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.27%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eFigure \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e illustrates the evolution of the patients monitored during the study. Analyzing only the patients who discontinued the use of medication, based on the reported side effects, we obtained headache in six patients (9.84%), breakthrough bleeding in 47 (77.08%), weight gain in eight (13.12%), persistence of pain in 23 (37.72%), nausea in six (9.84%), mastalgia in two (3.28%) and acne in one patient (1.64%).\u003c/p\u003e\n\u003cp\u003eGiven the complaints reported and the interruption of treatments, medication changes were proposed. Of these, 67 changes (46.52%) were made to medications in the same category and 77 changes (53.47%) to medications in a different category, as shown in Table \u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eSix medication changes involved GnRH agonists. Of the four patients who started the follow-up with GnRH agonists, three switched to combined hormonal contraceptives and one to progestins. Two patients changed to GnRH agonists, one used EP and the other P, previously.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ctable border=\"1\" id=\"Tab6\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMedication swaps after the first proposed treatment.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMedication Changes\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFrequency\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePercentage\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eFrom EP to EP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18.06%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eFrom EP to A\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.69%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eFrom EP to P\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30.57%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eFrom A to EP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.08%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eFrom A to P\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.69%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eFrom P to EP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18.75%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eFrom P to A\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.69%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eFrom P to P\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28.47%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eEP combined hormonal contraceptives, P progestins, A GnRH analog.\u003c/p\u003e\n\u003cp\u003eSource: the author (2022)\u003c/p\u003e\n\u003cp\u003eOf the 153 patients who did not interrupt the initial proposed treatment, 96 received P and 57 received EP. The average follow-up time for these patients was 38.91 months.\u003c/p\u003e\n\u003cp\u003eAmong the users of EP, the events that showed an association with the interruption of treatment were persistence of pain, with a relative risk of 1.65 (p\u0026thinsp;=\u0026thinsp;0.031) and breakthrough bleeding, with a relative risk of 2.76 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). All of this group who reported weight gain interrupted the treatment, but there was no statistical significance due to the low frequency of this complaint (p\u0026thinsp;=\u0026thinsp;0.1345). It was observed that the highest risk of interruption of EP occurs up to 9 months of treatment, with a relative risk of interruption of 2.32 (p\u0026thinsp;=\u0026thinsp;0.026). Treatment time above 10 months did not correlate with the risk of interruption.\u003c/p\u003e\n\u003cp\u003eAmong the users of P, the events that had a greater impact on the risk of interrupting treatment were breakthrough bleeding and heavy bleeding, with a relative risk of 1.35 (p\u0026thinsp;=\u0026thinsp;0.032). The time required for adaptation to treatment, and consequently not showing a correlation with medication interruption, was longer for P users. Up to 84 months of treatment, we have a relative risk of interruption of 1.74 (p\u0026thinsp;=\u0026thinsp;0.04), becoming non-significant thereafter.\u003c/p\u003e\n\u003cp\u003eWhen the two groups were compared, the patients who received P as the initial treatment had a significantly higher age range (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and had some reported personal medical history (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) compared to those who received EP.\u003c/p\u003e\n\u003cp\u003eThe multiple logistic regression analysis that correlated adverse events, type of medication, and treatment interruption showed that the complaint of breakthrough bleeding, weight gain, persistence of pelvic pain, and treatment with EP had a direct, significant, and independent association with clinical treatment interruption, adjusted for the complaint of headache, as shown in Table \u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ctable border=\"1\" id=\"Tab7\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 7\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMultiple analysis of side effects, type of medication used, and treatment interruption.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTreatment Type and Side Effect\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u0026quot;p\u0026quot; Value of Univariate Analysis\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eUnivariate Analysis OR (CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u0026quot;p\u0026quot; Value of Adjusted Analysis\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAdjusted Analysis OR (CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSpotting\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.267\u003c/p\u003e\n \u003cp\u003e(1.457\u0026ndash;3.528)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.672\u003c/p\u003e\n \u003cp\u003e(1.672\u0026ndash;4.269)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eEP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.725\u003c/p\u003e\n \u003cp\u003e(1.106\u0026ndash;2.692)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.995\u003c/p\u003e\n \u003cp\u003e(1.237\u0026ndash;3.219)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePersistence of Pain\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.043\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.619\u003c/p\u003e\n \u003cp\u003e(1.015\u0026ndash;2.582)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.043\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.670\u003c/p\u003e\n \u003cp\u003e(1.017\u0026ndash;2.743)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eWeight Gain\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.066\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.330\u003c/p\u003e\n \u003cp\u003e(0.946\u0026ndash;5.740)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.227\u003c/p\u003e\n \u003cp\u003e(1.237\u0026ndash;8.418)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHeadache\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.080\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.994\u003c/p\u003e\n \u003cp\u003e(0.849\u0026ndash;18.778)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.076\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.440\u003c/p\u003e\n \u003cp\u003e(0.855\u0026ndash;23.060)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eOR Odds Ratio, CI confidence interval, EP combined contraceptives containing estrogens and progestins.\u003c/p\u003e\n\u003cp\u003eConsidering only the patients who received EP, the multiple analysis showed that the adverse events of spotting and persistence of pain and the staging of minimal/mild endometriosis had a significant, direct and independent correlation with the interruption of treatment with EP. Infertility had an inverse correlation with the interruption of treatment. These data are shown in Table \u003cspan class=\"InternalRef\"\u003e8\u003c/span\u003e. The variables were adjusted for a treatment duration of fewer than 9 months, education level, and complaint of headache.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ctable border=\"1\" id=\"Tab8\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 8\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMultivariate analysis of the correlation between side effects, education, staging, and follow-up time with the risk of interrupting EP treatment.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSide Effect\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u0026quot;p\u0026quot; Value of Univariate Analysis\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eUnivariate Analysis OR (CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u0026quot;p\u0026quot; Value of Adjusted Analysis\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAdjusted Analysis OR (CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSpotting\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.267\u003c/p\u003e\n \u003cp\u003e(2028\u0026thinsp;\u0026minus;\u0026thinsp;8.978)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.432\u003c/p\u003e\n \u003cp\u003e(2.632\u0026ndash;27.014)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePersistence of Pain\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.117\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.769\u003c/p\u003e\n \u003cp\u003e(0.898\u0026ndash;3.610)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.388\u003c/p\u003e\n \u003cp\u003e(1.721\u0026ndash;23.714)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eInfertility\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.136\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.533\u003c/p\u003e\n \u003cp\u003e(0.234\u0026ndash;1.218)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.153\u003c/p\u003e\n \u003cp\u003e(0.037\u0026ndash;0.632)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eDuration of Follow-Up Less than 9 Months\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.041\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.291\u003c/p\u003e\n \u003cp\u003e(1.048\u0026ndash;10.335)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.067\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.550\u003c/p\u003e\n \u003cp\u003e(0.8990\u0026ndash;23.009)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eStaging Minimal/Mild\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.155\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.106\u003c/p\u003e\n \u003cp\u003e(0.755\u0026ndash;5.874)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.026\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.578\u003c/p\u003e\n \u003cp\u003e(1.233\u0026ndash;25.233)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eUniversity Degree\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.236\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.636\u003c/p\u003e\n \u003cp\u003e(0.331\u0026ndash;1.344)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.429\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.619\u003c/p\u003e\n \u003cp\u003e(0.188\u0026ndash;2.032)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHeadache\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.348\u003c/p\u003e\n \u003cp\u003e(0.469\u0026ndash;11.742)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.435\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.741\u003c/p\u003e\n \u003cp\u003e(0.217\u0026ndash;34.491)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eEP combined contraceptives containing estrogens and progestins OR Odds Ratio, CI confidence interval\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ctable border=\"1\" id=\"Tab9\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 9\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMultivariate analysis of the correlation between side effects, stage, and parity with the risk of treatment interruption with P.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSide Effect\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u0026quot;p\u0026quot; Value of Univariate Analysis\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eUnivariate Analysis OR (CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u0026quot;p\u0026quot; Value of Adjusted Analysis\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAdjusted Analysis OR (CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSpotting\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.057\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.775\u003c/p\u003e\n \u003cp\u003e(0.984\u0026ndash;3.203)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.638\u003c/p\u003e\n \u003cp\u003e(1.134\u0026ndash;6.136)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eWeight Gain\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.073\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.405\u003c/p\u003e\n \u003cp\u003e(0.923\u0026ndash;6.271)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.211\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.110\u003c/p\u003e\n \u003cp\u003e(0.655\u0026ndash;6.796)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntense Bleeding\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.086\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.062\u003c/p\u003e\n \u003cp\u003e(0.821\u0026ndash;20.104)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.308\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.443\u003c/p\u003e\n \u003cp\u003e(0.319\u0026ndash;37.174)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eStaging Minimal/Mild\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.206\u003c/p\u003e\n \u003cp\u003e(1.654\u0026ndash;16.382)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.078\u003c/p\u003e\n \u003cp\u003e(2.291\u0026ndash;28.482)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNulliparity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.171\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.538\u003c/p\u003e\n \u003cp\u003e(0.830\u0026ndash;2.852)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.239\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.667\u003c/p\u003e\n \u003cp\u003e(0.711\u0026ndash;3.907)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eP progestins OR Odds Ratio, IC confidence interval.\u003c/p\u003e\n\u003cp\u003eAs shown in Table \u003cspan class=\"InternalRef\"\u003e9\u003c/span\u003e, the adverse event that had a significant and independent correlation with treatment interruption with P was the presence of spotting. There was also a direct correlation with intraoperative endometriosis staged as minimal or mild.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe medication therapy for endometriosis consists of long-term treatment, like therapies for other chronic diseases such as diabetes mellitus and systemic arterial hypertension. The pain symptoms related to endometriosis cause a huge impact on quality of life and can be controlled with the use of these medications\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIt is natural for patients with endometriosis and pelvic pain to receive medication therapy until there is a desire for reproduction or menopause\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Thus, studies like this one, which seek to evaluate the efficacy and tolerability of the medications, are of extreme value.\u003c/p\u003e \u003cp\u003eIn the most recent recommendations for endometriosis management, we find a trend towards patient-focused treatment, their desires and symptoms, rather than endometriotic lesions, so medication therapy can be implemented without delay, even in the absence of histological confirmation of the disease\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Despite this approach gaining strength, all the patients in the present study obtained a diagnostic confirmation through surgery and a large part of them only started to be followed by the specialized sector after the procedure.\u003c/p\u003e \u003cp\u003eGiven the wide range of clinical manifestations and differential diagnoses, the time between the onset of symptoms and the definitive diagnosis with specialized endometriosis group monitoring is usually long\u003csup\u003e\u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. This study found an average of 4.8 years between these two events, with a non-parametric distribution, so the median of 2.5 years should be considered. In some scientific articles, the interval described is 6 to 8 years\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. The two most frequent symptoms were dysmenorrhea and dyspareunia, as reported by other studies\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe ovaries are the most affected areas by endometriosis, as shown in this study, which demonstrated ovarian endometriotic foci in 65.64% of the procedures. Definitive surgical treatments, such as hysterectomy and bilateral salpingo-oophorectomy, were exclusion criteria. Among the conservative approaches performed, the resection of endometrioma capsules (48.05%) and unilateral oophorectomies (25.81%) were the most frequent.\u003c/p\u003e \u003cp\u003eThe two most prescribed drug classes were combined contraceptives and isolated progestins, in their various doses and administration routes. There is no evidence that demonstrates superiority in pain control by a specific administration route. Considering the prolonged use of these medications, the administration route should facilitate treatment adherence and be in accordance with each patient's preferences\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eContinuous administration was preferred over cyclic administration for better control of dysmenorrhea. Periodic pauses were indicated only to control irregular bleeding and spotting.\u003c/p\u003e \u003cp\u003eCombined contraceptives and progestins seem to have similar effectiveness in controlling pain symptoms, achieving this result in two-thirds of patients\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAccording to Vercellini et al., combined contraceptives containing the lowest possible dose of ethinylestradiol and second-generation progestin can be considered first-line therapy in peritoneal lesions and endometriomas. Isolated progestins can be prescribed as an alternative to combined contraceptives when there are side effects, deep endometriosis, and in case of a contraindication to estrogen use, such as a high risk of thromboembolism\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. In fact, the group that received isolated progestins as a first-line therapeutic option was associated with a more advanced age and personal history of chronic diseases.\u003c/p\u003e \u003cp\u003eThe most frequent adverse event among patients who discontinued the proposed treatment were breakthrough bleedings, present in 77.08% of cases. Breakthrough bleedings were found in both groups and with a direct and independent association with medication interruption. This finding suggests that proper management of breakthrough bleedings may impact adherence and, consequently, therapeutic success.\u003c/p\u003e \u003cp\u003ePain persistence is expected in some patients using first-line therapies such as combined contraceptives and progestins. Some authors report a lack of response to these medications in up to 30% of patients, a therapeutic failure attributed to the progesterone resistance present in the disease's pathophysiology\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. In this study, pain persistence was significantly correlated with treatment interruption only in patients using EP.\u003c/p\u003e \u003cp\u003eEP treatments were significantly correlated with discontinuation, and this risk was higher in the first nine months of treatment. They are widely used to control symptoms of endometriosis, but various authors question their benefits. Some, for example, cite the lack of response in pain outside the menstrual period and dyspareunia, as well as the suspicion that EPs may induce the progression of endometriotic lesions\u003csup\u003e\u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe decrease in the rate of EP interruption over the months may represent patients' adaptation to the side effects of these drugs, so if there is resilience and good guidance on side effects at the beginning of treatment, the chances of good tolerability are higher.\u003c/p\u003e \u003cp\u003eIt is necessary to highlight that all patients underwent some surgical treatment, which allowed the histological diagnosis to be used as an inclusion criterion for the study. Thus, the benefits acquired by surgery should be considered.\u003c/p\u003e \u003cp\u003eThe choice of medical therapy for endometriosis is not simple. Several factors must be evaluated, such as main symptoms, reproductive desire, types of lesions found, side effects, comorbidities, and personal preferences of the patient. The importance of the patient's reception by the medical team with proper management of complications must also be emphasized.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe treatment with combined contraceptives has been associated with a higher risk of discontinuation than treatment with isolated progestins. This risk was significantly higher in the first 9 months of treatment. Among all the described complaints, breakthrough bleeding, weight gain, and persistence of pelvic pain had a direct, significant and independent association with medication discontinuation.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from all the participants.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll methods were carried out in accordance with relevant guidelines and regulations. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors confirm that the data supporting the findings of this study are available within the article. Raw data that support the findings of this study are available from the corresponding author, upon request.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo potential conflicts of interest were reported.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by the authors.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDenise Joffily Pereira da Costa Pinheiro and Ana Maria Gomes Pereira elaborated the structure of the study. Denise Joffily Pereira da Costa Pinheiro wrote the main manuscript text and prepared the figures and tables. Ana Maria Gomes Pereira did the statistical analyzes.\u003c/p\u003e\n\u003cp\u003eAll authors reviewed the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to express their gratitude to all patients assisted by our group.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFebrasgo (BR). Manual de endometriose 2014/2015. [Internet]. 2015 [cited 2022 jun 29]. Available from: http://professor.pucgoias.edu.br/SiteDocente/admin/arquivosUpload/13162/ma terial/Manual%20Endometriose%202015.pdf \u003c/li\u003e\n\u003cli\u003eNational Institute for Health and Care Excellence. Endometriosis: diagnosis and management. [Internet]. 2017 [cited 2022 jun 29]. Available from: https://www.nice.org.uk/guidance/ng73/resources/endometriosis-diagnosis- and-management-pdf-1837632548293 \u003c/li\u003e\n\u003cli\u003eMinistério da Saúde (BR). Protocolos Clínicos e Diretrizes Terapêuticas. Volume I. [Internet]. 2010 [cited 2022 jun 29]. Available from: http://bvsms.saude.gov.br/bvs/publicacoes/protocolos_clinicos_diretrizes_tera peuticas_v1.pdf \u003c/li\u003e\n\u003cli\u003eChapron C, Marcellin L, Borghese B, Santulli P. Rethinking mechanisms, diagnosis and management of endometriosis. Nature. 2019;15:666-682. \u003c/li\u003e\n\u003cli\u003eVercellini P, Vigano P, Somigliana E, Fedele L. Endometriosis:pathogenesis and treatment. Nat. Rev. Endocrinol. 2014;10:261-275. \u003c/li\u003e\n\u003cli\u003eBecker CM, Bokor A, Heikinheimo O, Horne A, Janses F, Kiesel L, et al. ESHRE guideline: endometriosis. Hum Rep Open. 2022;1-26. \u003c/li\u003e\n\u003cli\u003eVercellini P, Buggio L, Frattaruolo MP, Borghi A, Dridi D, Somigliana E. Medical treatment of endometriosis-related pain. Best Pract Res Clin Obstet Gynaecol. 2018;51:68-91. \u003c/li\u003e\n\u003cli\u003eAmerican Society for Reproductive Medicine. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67(5):817-821. \u003c/li\u003e\n\u003cli\u003eFalcone T, Flyckt R. Clinical Management of Endometriosis. Obstet Gynecol. 2018;131(3):557-71. \u003c/li\u003e\n\u003cli\u003eMcLeod BS, Retzloff MG. Epidemiology of endometriosis: an assessment of risk factors. Clin Obstet Gynecol. 2010;53(2):389-96. \u003c/li\u003e\n\u003cli\u003eKondo W, Ribeiro R, Trippia C; Zomer MT. Endometriose profunda infiltrativa: distribuição anatômica e tratamento cirúrgico. Rev Bras Ginecol Obs. 2012;34(6):278-84. \u003c/li\u003e\n\u003cli\u003eZondervan KT, Phil D, Becker CM, Missmer SA. Endometriosis. N Engl J Med. 2020;382:1244-56. \u003c/li\u003e\n\u003cli\u003eNácul AP; Spritzer PM. Current aspects on diagnosis and treatment of endometriosis. Rev Bras Ginecol Obstet [Internet]. 2010 [cited 2022 jul15];32(6). Available from: https://doi.org/10.1590/s0100- 72032010000600008 \u003c/li\u003e\n\u003cli\u003eWorking group of ESGE, ESHRE and WES, Keckstein J, Becker CM, Canis M, et al. Recommendations for the surgical treatment of endometriosis. Part 2: deep endometriosis. Hum Reprod Open. 2020;12(1):1-25. \u003c/li\u003e\n\u003cli\u003eMIinistério da Saúde (BR). Protocolos clínicos e diretrizes terapêuticas endometriose goserrelina, leuprorrelina, triptorrelina, danazol. [Internet]. 2006 [cited 2022 jun 29]. Available from: http://bvsms.saude.gov.br/bvs/saudelegis/sctie/2006/prt0069_01_11_2006_co mp.html \u003c/li\u003e\n\u003cli\u003eBulun SE, Yilmaz BD, Sison C, Miyazaki K, Bernardi L, Liu S, Kohlmeier A, Yin P, Milad M, Wei J. Endometriosis. Endocrine Reviews. 2019;40(4):1048- 1079. \u003c/li\u003e\n\u003cli\u003eBarbara G, Buggio L, Facchin F, Vercellini P. Medical Treatment for Endometriosis: Tolerability, Quality of Life and Adherence. Front Glob Womens Health. 2021;2:729601. \u003c/li\u003e\n\u003cli\u003eKalaitzopoulos DR, Samartzis N, Kolovos GN, Mareti E, Samartzis P, Eberhard M, et al. Treatment of endometriosis: a review with comparison of 8 guidelines. BMC Women\u0026rsquo;s Health. 2021;21:397. \u003c/li\u003e\n\u003cli\u003eZorbas KA, Economopoulos KP, Vlahos NF. Continuous versus cyclic oral contraceptives for the treatment of endometriosis: a systematic review. Arch Gynecol Obstet. 2015; 292(1):37\u0026ndash;43. \u003c/li\u003e\n\u003cli\u003eSchindler AE. Dienogest in long-term treatment of endometriosis. Int J Womens Health. 2011;3:175\u0026ndash;84. \u003c/li\u003e\n\u003cli\u003eBuggio L, Somigliana E, Barbara G, Frattaruolo MP, Vercellini P. Oral and depot progestin therapy for endometriosis: towards a personalized medicine. Expert Opin Pharmacother, 2017, 18(15):1569\u0026ndash;1581. https://doi.org/10.1080/14656566.2017.13 81086 PMID: 28914561 \u003c/li\u003e\n\u003cli\u003eRemorgida V, Abbamonte LH, Ragni N, Fulcheri E, Ferrero S. Letrozole and Desogestrel-only contraceptive pill for the treatment of stage IV endometriosis. Aust N Z J Obstet Gynaecol, 2007, 47(3):222\u0026ndash;225. https://doi.org/10.1111/j.1479-828X.2007. 00722.x PMID: 17550490 \u003c/li\u003e\n\u003cli\u003eVercellini P, Aimi G, Panazza S, Giorgi OD, Pesole A, Crosignani PG. A levonorgestrel-releasing intrauterine system for the treatment of dysmenorrhea associated with endometriosis: a pilot study. Fertil Steril. 1999;72(3): 505\u0026ndash;508. \u003c/li\u003e\n\u003cli\u003eFedele L, Bianchi S, Zanconato G, Portuese A, Raffaelli R. Use of a levonorgestrel-releasing intrauterine device in the treatment of rectovaginal endometriosis. Fertil Steril. 2001;75(3):485\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003ePetta CA, Ferriani RA, Abrao MS, Hassan D, Silva JCR, Podgaec S, et al. Randomized clinical trial of a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the treatment of chronic pelvic pain in women with endometriosis. Hum Reprod. 2005;20(7):1993\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eOpenEpi online version. [Internet]. 2013 [cited 2022 jul15] Available from: http://www.openepi.com/DiagnosticTest/DiagnosticTest.htm \u003c/li\u003e\n\u003cli\u003eSantos TMV, Pereira AMG, Lopes RGC, Depes DB. Tempo transcorrido entre o início dos sintomas e o diagnóstico de endometriose. Einstein. 2012;10(1):39-43. \u003c/li\u003e\n\u003cli\u003eArruda MS, Petta CA, Abrão MS, Benetti-Pinto CL. Time elapsed from onset of symptoms to diagnosis of endometriosis in a cohort study of Brazilian women. Hum Reprod. 2003;18(4):756-9. \u003c/li\u003e\n\u003cli\u003eSoliman AM, Fuldeore M, Snabes MC. Factors associated with time to endometriosis diagnosis in the United States. J Womens Health. 2017;26(7):788-97. \u003c/li\u003e\n\u003cli\u003eVercellini P. Endometriosis: What a pain it is. Semin Reprod Endocrinol.1997;15(3):251-61. \u003c/li\u003e\n\u003cli\u003eVercellini P, Buggio L, Berlanda N, Barbara G, Somigliana E, Bosari S. Estrogen-progestins and progestins for the management of endometriosis. Fertil Steril. 2016;106(7):1552-71. \u003c/li\u003e\n\u003cli\u003eDonnez J, Dolmans MM. Endometriosis and medical therapy: from progestogens to progesterone resistance to GnRH antagonists: a review. J Clin Med. 2021;10(5):1085. \u003c/li\u003e\n\u003cli\u003eCasper RF. Progestin-only pills may be a better first-line treatment for endometriosis than combined estrogen-progestin contraceptive pills. Fertil Steril. 2017;107(3):533-36. \u003c/li\u003e\n\u003cli\u003eChapron C, Souza C, Borghese B, Lafay-Pillet MC, Santulli P, Bijaoui G, et al. Oral contraceptives and endometriosis: the past use of oral contraceptives for treating severe primary dysmenorrhea is associated with endometriosis, especially deep infiltrating endometriosis. Hum Reprod. 2011;26(8):2028\u0026ndash;35. \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":"bmc-womens-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmwh","sideBox":"Learn more about [BMC Women's Health](http://bmcwomenshealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmwh/default.aspx","title":"BMC Women's Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"endometriosis, pharmacological treatment, side effects, tolerability","lastPublishedDoi":"10.21203/rs.3.rs-2667012/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2667012/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eEndometriosis is a chronic inflammatory disease that occurs in women of reproductive age. Much of the treatment involves hormone therapy that suppresses the proliferation of endometriosis lesions.\u003c/p\u003e\n\u003ch2\u003eObjective\u003c/h2\u003e\n\u003cp\u003eto compare discontinuation rates of pharmacological treatment with estrogen-progestins and progestins medications. The secondary objective is to evaluate the main side effects of these drugs in patients with endometriosis.\u003c/p\u003e\n\u003ch2\u003eMethods\u003c/h2\u003e\n\u003cp\u003ethis retrospective study analyzed data from 330 patients who attended the Hospital of the State Public Servant of São Paulo from August 1999 to September 2020 and received pharmacological treatment for endometriosis. The data were obtained by review of the files of medical appointments with specialized staff.\u003c/p\u003e\n\u003ch2\u003eResults\u003c/h2\u003e\n\u003cp\u003ethe median treatment time was 18 months, ranging from 1 to 168 months, and 177 patients interrupted the proposed treatment. The combined contraceptives with estrogens and progestins were significantly linked to treatment interruption, with a relative risk of 1,99 (p = 0,005). The most important side effects that resulted in treatment interruption were pain persistence (p = 0,043), weight gain (p = 0,017) and spotting (p \u0026lt; 0,001).\u003c/p\u003e","manuscriptTitle":"Tolerability of endometriosis medical treatment: a comparison between combined hormonal contraceptives and progestins","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-03-30 22:36:28","doi":"10.21203/rs.3.rs-2667012/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2023-08-07T11:15:44+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-08-06T14:59:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"12c8378b-cf7a-46f1-89ca-1e3aa674afa3","date":"2023-07-15T19:16:20+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-05-15T08:44:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"10c34384-1214-4a8f-9384-ed47a3cad9e7","date":"2023-04-30T06:18:43+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-04-07T09:18:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-04-02T04:38:22+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2023-03-29T10:55:29+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-03-29T10:51:15+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Women's Health","date":"2023-03-07T21:08:53+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-womens-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmwh","sideBox":"Learn more about [BMC Women's Health](http://bmcwomenshealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmwh/default.aspx","title":"BMC Women's Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8bf8405c-a54a-4be4-a78a-f70a8c401831","owner":[],"postedDate":"March 30th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-09-25T15:02:26+00:00","versionOfRecord":{"articleIdentity":"rs-2667012","link":"https://doi.org/10.1186/s12905-023-02647-y","journal":{"identity":"bmc-womens-health","isVorOnly":false,"title":"BMC Women's Health"},"publishedOn":"2023-09-23 15:00:38","publishedOnDateReadable":"September 23rd, 2023"},"versionCreatedAt":"2023-03-30 22:36:28","video":"","vorDoi":"10.1186/s12905-023-02647-y","vorDoiUrl":"https://doi.org/10.1186/s12905-023-02647-y","workflowStages":[]},"version":"v1","identity":"rs-2667012","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2667012","identity":"rs-2667012","version":["v1"]},"buildId":"WvIrzKhiLBfengagbw6Ux","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}