Pharmacological management of obesity in adults: a systematic review and meta-analysis of randomized controlled trials to evaluate the efficacy and safety of obesity management medications

Pharmacological management of obesity in adults: a systematic review and meta-analysis of randomized controlled trials to evaluate the efficacy and safety of obesity management medications | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Pharmacological management of obesity in adults: a systematic review and meta-analysis of randomized controlled trials to evaluate the efficacy and safety of obesity management medications Andreea Ciudin, Barbara McGowan, Andreea Ciudin, Jennifer Baker, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6449183/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Oct, 2025 Read the published version in Nature Medicine → Version 1 posted You are reading this latest preprint version Abstract Background : There are different types of obesity management medications (OMMs) are available but their effectiveness in reducing body weight and preventing or reversing obesity-related complications (ORC) can vary significantly. We therefore evaluated the efficacy and safety of OMMs in the treatment of obesity and related complications. Methods : This systematic review and network meta-analysis included randomized clinical trials (RCTs) with at least a 48-week treatment period, comparing OMM versus placebo or active comparators in patients with obesity (body mass index; BMI ≥30 kg/m 2 ) or overweight (BMI ≥25 kg/m 2 ). A Medline and Embase search was performed up to January 31, 2025 for RCTs on OMMs adopted by at least one EASO member country in adults. The primary endpoint was the percentage of total body weight loss (TBWL%) at the end of the study. Secondary endpoints included TBWL% at 1, 2, and ≥3 years, lipid profile, blood pressure, HbA1c, fasting plasma glucose, mental health, serious adverse events (SAE), quality of life, cardiovascular morbidity and mortality, obesity-associated comorbid condition remission, and all-cause mortality. Weighted mean difference and 95% confidence intervals (CI) were estimated for continuous variables. Mantel-Haenzel odds ratios and 95% CIs were estimated for categorical variables, using random effect models. The study was registered with PROSPERO (registration number CRD42024625338). Findings There were 55 clinical trials identified, they included orlistat (n=21), semaglutide (n=12), liraglutide (n=9), tirzepatide (n=6), naltrexone/bupropion (n=5), and phentermine/topiramate (n=2), enrolling 62,861 patients (33,986 and 28,804 with active compound and placebo, respectively). At the primary endpoint (mean follow-up duration 68 weeks), all OMMs showed a significantly greater TBWL% versus placebo (all p<0.0001). The estimated endpoint TBWL% was greater than 10% for semaglutide and tirzepatide. The type of OMM impacted the magnitude of changes in the secondary outcomes examined. Serious adverse effects (SAE) were reported in most studies, and OMMs were not associated with an increased risk of SAE compared to placebo, except for naltrexone/bupropion. Semaglutide was associated with a lower risk of mortality. Interpretation : The present findings support the need to tailor OMMs to the presence and severity of ORC, as different OMMs produce varying degrees of weight loss and have differing impacts on specific ORCs. Health sciences/Endocrinology/Endocrine system and metabolic diseases/Obesity Biological sciences/Drug discovery/Pharmaceutics Obesity Management Medications Network Meta-Analysis Obesity Overweight Efficacy Safety Figures Figure 1 Figure 2 INTRODUCTION The prevalence of overweight and obesity is either increasing or at a level that is too high in many countries worldwide, leading to a rise in metabolic and cardiovascular diseases, cancer, and overall mortality 1 . Considering the high prevalence of obesity and its harmful impact on health 2 , its management represents a complex medical and economic 2 challenge for all healthcare systems. Currently, lifestyle intervention is the first-line treatment for people with obesity. However, its mid- and long-term effects and adherence is limited 3 , 4 . Obesity is an adipose-based chronic disease driven by biological mechanisms, resulting in dysregulation and/or excess accumulation of adipose tissue 5 . The biology of obesity includes genetic predisposition, neurohormonal signaling disruptions (particularly in the hypothalamus), and alterations in appetite-regulating hormones 6 – 8 . Furthermore, the body defends against fat loss through mechanisms including reduced resting energy expenditure and increased hunger, making long-term weight maintenance challenging. As a result, lifestyle interventions alone—such as diet and exercise—are often insufficient, and effective management typically requires a combination of strategies to address the underlying biology of obesity. Current guidelines recommend that, particularly for high-risk people with severe obesity or obesity-related complications (ORC), lifestyle programs can be combined with obesity management medications (OMMs) or metabolic bariatric surgery (MBS) 9 – 12 . Recent advances in the biology of obesity have led to the development of novel medications, providing healthcare professionals with a broader range of therapeutic options 13 . Due to regulatory requirements, newer medications are supported by clinical trials on substantial numbers of patients, often including studies on longer-term cardiovascular outcomes 14 , 15 . However, the availability of head-to-head comparisons between different OMMs in randomized controlled trials (RCTs) is still limited 16 , which makes assessment of differences in efficacy and safety across available molecules is challenging. The method of network meta-analysis (NMA), which provides indirect comparisons of efficacy and safety, can overcome this challenge. Several NMAs on different therapeutic options for overweight and obesity have been published in the last few years 17 , 18 , but they did not include more recently available OMMs, such as tirzepatide 18 , 19 , or included medications not approved for the treatment of overweight/obesity (e.g., metformin, SGLT2 inhibitors, or GLP-1 agonists such as dulaglutide, etc.) 18 . The European Association for the Study of Obesity (EASO) has developed the first GRADE-based (Grading of Recommendations Assessment, Development and Evaluation) treatment algorithm for the pharmacological management of obesity, as outlined in the 2024 EASO framework 20 . This algorithm was created using the findings of the present network meta-analysis (NMA), which aims to provide healthcare professionals involved in obesity care with a comprehensive overview based on published data on the efficacy and safety of all obesity management medications (OMMs) available in Europe until January 31, 2025. MATERIALS AND METHODS This NMA is reported following the criteria of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement 16 (Table 1 S). Study search and selection The protocol for this meta-analysis and NMA was published on the PROSPERO website ( https://www.crd.york.ac.uk/prospero/#recordDetails ; registration number: CRD42024625338) and in a previous article 21 . The present analysis included all placebo-or active- RCTs that enrolled adults (≥ 18 years) with obesity (body mass index; BMI ≥ 30 kg/m 2 ) or overweight (BMI > 25 kg/m 2 ), with a treatment duration of at least 48 weeks, which compared OMMs with the specific indication of obesity treatment with either placebo or other OMM. Further, the RCTs needed to be performed on OMMs available in at least one EASO member country as of January 31, 2025. The OMMs and doses included were: orlistat (360 mg), phentermine plus topiramate (P/T, 15/92 mg), naltrexone plus bupropion (N/B, 32/360 mg), liraglutide (3.0 mg), semaglutide (2.4 mg), and tirzepatide (10–15 mg). A Medline and Embase search was performed up to January 31, 2025; detailed information on the search strategy and keywords used is reported in Table 2 S of the Supplementary Materials. Duplicate records were removed with EndNote X9 (Clarivate Analytics, Philadelphia, PA, USA). Data extraction Information on the baseline characteristics of the samples enrolled (age, gender, proportion of patients with T2D, baseline BMI, total body weight loss (TBWL%), waist circumference, body composition, proportion of patients achieving at least 5%, 10%, 15%, 20%, and 25% body weight reduction, remission or improvement/resolution of ORC, serious adverse events (SAE), mortality, major adverse cardiovascular events (MACE), fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), lipid profile, estimated glomerular filtration rate (eGFR), creatinine, albuminuria, mental health parameters, and quality of life (QoL). Two authors performed data extraction independently (B.R., E.M), and conflicts were resolved by a third investigator (M.M.). Quality assessment The risk of bias was assessed using the Cochrane recommended tool to determine the risk of bias in RCTs 19 . The risk of bias was described and evaluated in seven specific domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases. The results of these domains were graded as low, high, or uncertain risk of bias. Two researchers (B.R. and E.M.) independently assessed the risk of bias in individual studies, with discrepancies resolved by a third researcher (M.M.). Data analysis The principal endpoint was TBWL% at the end of treatment; secondary endpoints were: a) TBWL% at 52 weeks, 53-104 weeks, 105-156 weeks, >156 weeks. b) Change in endpoint BMI and waist circumference. c) Change in total Fat Mass (FM), Subcutaneous Fat Mass (SFM) and Visceral Fat Mass (VFM). d) Change in Fat-Free Mass (FFM). e) The proportion of patients achieving at least 5, 10, 15, 20%, and 25% body weight reduction f) Type 2 Diabetes (T2D), Hypertension (HTN), and Dyslipidemia (DL) remission. Type 2 diabetes remission was defined as HbA1c< 6.5% at endpoint. g) MASH (metabolic dysfunction–associated steatohepatitis) resolution (defined as no steatotic liver disease without worsening of fibrosis), improvement of liver fibrosis (defined as a decrease of at least one fibrosis stage without worsening of MASH 22 ). Obstructive Sleep Apnea Syndrome (OSAS) resolution (defined as Apnea-Hypopnea Index (AHI) <5 or AHI of 5 to 14), and improvement of Knee Osteoarthritis (KOA) (improvement in pain/physical functioning items of any validated scale assessing quality of life in patients with KOA). h) Reduction of hospital admission for heart failure (HHF), considering only studies in which these events were formally adjudicated. i) Any SAE. j) All-cause mortality. k) MACE (composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular mortality), considering only studies in which these events were formally adjudicated. l) Endpoint FPG, HbA1c, lipid profile, eGFR, creatinine, and albuminuria. m) Change in mental health parameters. n) Quality of Life (QoL). All the endpoints, except point a), were collected at the end of the trials. Statistical analyses Mean and 95% confidence intervals (95% CI) for continuous variables and Mantel-Haenzel Odds Ratio [MH-OR] for categorical variables were calculated, using random effect models. When data were reported as least-squares mean and standard error (SE), the standard deviation (SD) was obtained for each group using the following formula: SD= √(number of patients)*(CI upper limit – CI lower limit)/3.92 and SD= √(number of patients)*SE, respectively (http://handbook-5-1.cochrane.org/chapter_7/7_7_3_2_obtaining_standard_deviations_from_standard_errors_and.htm). Prespecified subgroup analyses were performed for the following baseline variables: different OMMs, BMI categories (mean BMI at the enrolment 40 kg/m 2 ), T2D (RCT enrolling at least 75% of patients with diabetes), prediabetes 23 , previous established cardiovascular disease (CVD), heart failure (HF), KOA, MASLD, and OSAS. A further subgroup analysis was performed only for body weight parameters (i.e., TBWL%, waist circumference, BMI, and proportion of patients achieving at least 5, 10, 15, 20, and 25% of body weight reduction) in RCTs specifically designed for body weight reduction. Table 3S reports the principal endpoints (together with the others considered critical) for all these subpopulations of patients with obesity. Traditional meta-analyses were performed for the primary endpoint and the other outcomes if they were reported in less than 10 RCTs. Heterogeneity was assessed by using I 2 statistic. Random-effect models were applied for all the analyses reported above. We performed a NMA 24 for all the outcomes listed above to examine differences across individual OMMs concerning their effects on primary and secondary endpoints. These analyses allow indirect comparisons when direct trials are unavailable, using differences from common comparators, and then combining direct and indirect comparisons for a final estimate of effects. The reference category was placebo. We performed NMA within a pairwise modeling (GPM) framework using the software program MetaXL (www.epigear.com). H values were calculated to test consistency between direct and indirect evidence; H<3 indicates minimal inconsistency of treatment effects. All other analyses were performed using Review Manager (RevMan), Version 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). The GRADE methodology 11 was used to assess the quality of the body of retrieved evidence for the principal endpoint, with the GRADEpro GDT software (GRADEpro Guideline Development Tool. McMaster University, 2015. Available from gradepro.org). RESULTS Retrieved trials Figure 1S of Supporting Materials reports the trial flow summary showing the results of the search of Medline and Embase databases. Table 4 S of Supplementary Materials reports which trials were excluded (n = 7) after reading the full text. Out of 55 clinical trials, performed with orlistat (n = 21), semaglutide (n = 12), liraglutide (n = 9), tirzepatide (n = 6), N/B (n = 5), and P/T (n = 2), enrolling 62,861 patients (33,986 and 28,804 with active compound and placebo, respectively) were analyzed. All RCTs were placebo-controlled studies, except for one trial that reported multiple comparisons (i.e., liraglutide versus placebo or orlistat); therefore the overall number of available comparisons was 56. The main characteristics of the included RCTs are reported in Table 5S of the Supporting Materials. No studies reported a mean baseline BMI < 30 kg/m 2 ; one trial disclosed subgroup analyses for the primary endpoint across different BMI categories 25 . The quality of studies was heterogeneous (Figs. 2 S and 3S of Supporting Materials). Most of the included RCTs were double-blind (66%), with few trials inadequately reporting attrition and/or description of allocation or blinding of assessors (29%). Out of 56 treatment arms, 55 comparisons were performed versus placebo. All, except five 15 , 26 – 29 , reported information on TBWL% at the endpoint. Only one head-to-head comparison 16 between different OMMs was identified (i.e., liraglutide vs. orlistat), showing a greater efficacy for liraglutide than for orlistat (WMD: 3.80 [0.73, 6.87]%, p = 0.020). Network meta-analysis 1) Effects on body weight 1.1 TBWL% at different time points Figure 1 reports the number of available RCTs for each comparison, while Fig. 2 and Table 1 show the efficacy results with respect to TBWL% at the end of the different time points (52, 104, > 156 weeks, and at end of the study), based on the NMA. At the primary endpoint (n = 50 comparisons, with no evidence of inconsistency; H = 1.00), all OMM yielded a statistically significant greater TBWL% in comparison with placebo. The estimated TBWL% was greater than 10% only for semaglutide and tirzepatide (Fig. 2 , panel A). Details of direct and indirect estimates are reported in Table 6S. A visual analysis of funnel plots did not suggest publication bias (Fig. 4S). At 52 weeks (n = 50 comparisons, with evidence of inconsistency; H = 4.01), all treatments showed a significantly greater TBWL% versus placebo, except for orlistat (Fig. 2 , Panel B). Similar to the endpoint analyses, only semaglutide and tirzepatide achieved a TBWL% of at least 10% (Fig. 2 , Panel B). Details of direct and indirect estimates are reported in Table 7S. A limited number of comparisons were possible at 53 to 104 weeks (n = 13; H = 1.00; Fig. 2 panel C and Table 8S), 105–156 weeks (n = 3, Fig. 5S) and > 156 weeks (one trial 30 with orlistat reporting a 3% TBWL in comparison with placebo, and one subgroup analysis 31 of a trial with tirzepatide 32 reporting 19.3% TBWL). For all assessed treatments, the estimated efficacy at the endpoint was similar to that observed at 52 weeks and 104 weeks. 1.2 Waist circumference, BMI, and proportion of patients achieving at least 5%, 10%, 15%, 20%, and 25% of TBWL Table 1 and Figs. 6S and 7S report results of the effects of each OMM on endpoint waist circumference and BMI (% reduction from baseline). Tirzepatide and semaglutide were associated with a greater reduction of both waist circumference and BMI. Trials on P/T did not report information on these two endpoints and thus were not included in these analyses. The proportion of patients achieving different thresholds of TBWL% are reported in Table 1 and Figs. 8S and 9S. Patients treated with OMMs, except for orlistat, were more likely to achieve a TBWL of at least 5% in comparison with placebo. A higher degree of TBWL (> 20%) was observed only with semaglutide and tirzepatide and, to a lesser extent, with liraglutide. Only tirzepatide was associated with a greater proportion of patients achieving at least 25% TBWL reduction (Fig. 9S, Panel E). Five trials 16 , 32 – 35 reported results on body composition parameters assessed using heterogeneous methods (often in a smaller subgroup of included patients). Two studies on semaglutide 32 , 34 did not report any information about dispersion measurements and, therefore were not included in any formal analyses. Semaglutide showed a greater reduction of total 34 and regional visceral fat mass 34 , 35 and a greater increase in total lean body mass 35 in comparison with placebo. Tirzepatide was associated with a greater reduction of total body fat mass and a significantly lower reduction in total fat-free mass 32 ; similar results, despite to a lesser extent, were observed with liraglutide 16 , 33 . When subdividing trials by baseline BMI (< 30; 30-34.9; 35-39.9; ≥40.0 kg/m 2 ; Table 2 ), no RCTs on OMMs reported results for patients with overweight; only two OMMs (semaglutide and tirzepatide) provided data for class III obesity (BMI ≥ 40.0 kg/m 2 ; Table 3 and Figs. 44S-46S). The majority of information on the effects of each included OMM was available for the class II obesity (35-39.9 kg/m 2 ) category, which showed the highest body weight reduction for tirzepatide and semaglutide (TBWL% >10%). A further post-hoc subgroup analysis was performed for RCTs specifically designed for body weight reduction. The results of these analyses, after excluding RCTs 14 , 15 , 22 , 29 , 36 – 38 with a primary endpoint other than body weight reduction, are reported in Table 4 and Figs. 10S-13S. Results from these analyses were similar to those of the primary endpoint analysis. 2) Effects on glycemic control, blood pressure and lipid profile Data were obtained considering all RCTs reporting data on each metabolic endpoint, irrespective of the proportion of patients with T2D or prediabetes. Table 1 and Figs. 14-21S report results for metabolic parameters (n = 24, 32, 29, 35, and 32 RCTs for HbA1c, FPG, total and HDL-cholesterol, and triglycerides, respectively) and blood pressure (n = 35 and 29 RCTs for systolic and diastolic blood pressure, respectively). Tirzepatide produced a significantly greater reduction in HbA1c in comparison with other OMMs, whereas liraglutide and semaglutide were associated with a greater reduction of FPG in contrast with the other OMMs (Figs. 14S and 15S). T2D remission was reported in a low number of RCTs (n = 5) and, therefore, we performed traditional meta-analyses showing significant results for N/B, liraglutide, semaglutide, and tirzepatide (Fig. 16S and 17S). Eight trials reported data on incident T2D, showing a positive effect for liraglutide, P/T, and semaglutide, but not orlistat (Fig. 25S). Semaglutide and tirzepatide, but not liraglutide, were associated with a higher chance of restoring normoglycemia in patients with pre-existing glycemic alterations (Fig. 26S). Orlistat was associated with the highest total cholesterol reduction, and statistically significant results versus placebo were also obtained for P/T and liraglutide. Tirzepatide, N/B, and liraglutide were associated with a greater increase of HDL-cholesterol values; semaglutide, P/T, and orlistat resulted in a significant reduction of triglyceride circulating levels (Figs. 18S and 19S). Table 1 and Fig. 20S show the effects of each OMM on blood pressure, with N/B associated with a significant increase in systolic, but not diastolic, blood pressure. All the other OMMs exerted significant favorable effects on systolic blood pressure and some (P/T, tirzepatide, and orlistat) on diastolic blood pressure. Only a few RCTs reported data on hypertension and dyslipidemia remission, with clinically inconsequential effects (Figs. 21S and 22S). 3) Effects on cardiovascular morbidity and mortality Thirty-two, 36, and 7 RCTs reported information on (externally adjudicated) MACE, cardiovascular mortality, and HHF, respectively (Figs. 27S and 29S). Table 1 and Figs. 25S and 26S show results on these endpoints. Only semaglutide was associated with a significantly lower risk for MACE, with all OMMs reporting odds ratios below 1, except for PT (OR: 2.00 [0.18; 22.1], p > 0.50; Fig. 28S, panel B). No information on cardiovascular mortality was reported for P/T. Semaglutide and N/B were associated with a lower risk for cardiovascular mortality (Fig. 28S, panel C). HHF was significantly reduced by tirzepatide (n = 2 RCTs), whereas semaglutide (n = 4 RCTs) showed a non-signifcant trend toward a reduction. Liraglutide reported zero events in both arms, and therefore, the overall risk was not estimable (Fig. 29S). 4) Effects on quality of life and mental health Only a few trials reported data on quality of life, using different scales (8, 2, 7, and 1 with IWQOL-Lite, SF-36 General Health, SF-36 Physical Role Functioning, SF-36 Physical Components, respectively). The paucity of data did not support a NMA, but only traditional meta-analyses (Table 1 and Fig. 30S of Supplementary Materials). N/B and semaglutide were associated with an improvement of IWQOL versus placebo (Fig. 30S panel A). Only one active-controlled trial (liraglutide versus orlistat) reported data on IWQOL, showing better scores for liraglutide 16 . No other significant differences were observed across the remaining scales, except for semaglutide, which showed improved scores in the Short Form-36 Physical Functioning domain (Fig. 30S, panel C). Suicide attempts and major depression were reported as SAE (with no external adjudication) in a high number of RCTs (Fig. 31S, panel C and D). No significant association was observed between treatment with any OMM and the risk for either suicide attempt or depression, except for N/B, which was associated with a significantly lower risk of depression (Table 1 and Fig. 32S, panel C and D). Few studies reported about anxiety (n = 9), thus a NMA was not possible, and the standard meta-analysis did not show a significant association for any OMM (Fig. 30S). 5) Safety outcomes Results on all-cause mortality are reported in Table 1 , Figs. 27S and 28S. Semaglutide was associated with a lower risk of mortality; the other OMMs did not show any significant effect on this endpoint (Fig. 25S). SAEs (Table 1 and Figs. 31S and 32S) were reported in most included studies, and no OMM was significantly associated with an increased risk of SAEs in comparison with placebo, except for N/B. The treatment discontinuation rate was similar to that observed in the placebo arms, with no significant between-group differences (Figs. 31S and 32S). 6) GRADE evaluation for the primary endpoint The evaluation of the quality of evidence for the primary endpoint (i.e., TBWL%) was rated as “high” (Table 9S) for each OMM. Subgroup analyses for patients’ pre-existing conditions As reported in a previously published article 39 , EASO identified several subgroups of patients with pre-existing comorbid conditions (Table 3 S of Supplementary Materials). In this section, we analyzed the effects of each OMM on several prespecified critical outcomes in specifically designed RCTs or in reported subgroups of patients affected by that comorbid condition 21 . 1) Established CVD Only two trials, one with semaglutide 14 and one with N/B 15 , were designed to explore the effects on cardiovascular safety in patients with obesity. Information on TBWL% was available only for semaglutide, with results similar to those obtained in non-cardiovascular outcome trials (8.7%; Table 2 ). Semaglutide, but not N/B, was associated with a significantly lower risk of MACE and acute myocardial infarction in patients with established cardiovascular disease, whereas cardiovascular mortality was reduced by N/B but not by semaglutide. In contrast, both OMM reported a significantly lower risk for all-cause mortality compared to placebo (Table 2 ). The GRADE evaluation of the evidence retrieved for the primary endpoint (MACE, Table S3) was rated as “high” and “moderate” for semaglutide and NB, respectively (Table S9). 2) Hospitalization for heart failure (HHF) Three trials (two with semaglutide 40 , 41 and one with tirzepatide 38 ) included patients with previously diagnosed HF. The effects of the two medications for TBWL% were not different from other non-cardiovascular outcome trials, despite a slightly less efficacy for tirzepatide (11.7 vs 16.5%; Figs. 35S and 36S). The risk of HHF was significantly reduced for both semaglutide and tirzepatide, with increased specific-disease quality of life questionnaires (KCCQ) scores and performances at 6-minute walking test. No relevant effects on all-cause and cardiovascular mortality were observed for the two medications (Table 2 ; Figs. 35 and 36S). The GRADE evaluation of the evidence retrieved for the primary endpoint (HHF, Table S3) was rated as “high” for both tirzepatide and semaglutide (Table S9). 4) Prediabetes Two studies (one with liraglutide and one with semaglutide) were specifically designed for patients affected by overweight/obesity and prediabetes 42 , 43 , and two more studies (one with orlistat 30 and one with tirzepatide 31 ) reported a longer-term analysis on a subgroup of patients with prediabetes. All those four OMMs (orlistat, liraglutide, semaglutide, and tirzepatide) are capable of effectively reducing TBWL%, HbA1c, and FPG in patients with prediabetes. Orlistat, liraglutide and tirzepatide, but not semaglutide, were associated with a significant reduction of incident diabetes. Normoglycemia restoration was more likely to be achieved in the interventional group for liraglutide, semaglutide, and tirzepatide, but not orlistat, in comparison with placebo (Table 2 , and Fig. 37S). The GRADE evaluation of the evidence retrieved for the primary endpoint (normoglycemia restoration, Table S3) was rated as “high” for all OMM reporting this outcome, except for orlistat (“low”; Table S9). 5) Type 2 diabetes Eleven trials have been performed in patients with diabetes (Fig. 38S). Tirzepatide was associated with a greater effect on TBWL%; semaglutide, tirzepatide, and N/B were all associated with significant effects on HbA1c, FPG, and diabetes remission rate. Liraglutide reported significant results only for diabetes remission rate (Table 2 and Fig. 39S). The GRADE evaluation of the evidence retrieved for the primary endpoint (diabetes remission, Table S3) was rated as “high” for liraglutide, N/B, semaglutide, and tirzepatide (Table S9). 6) Metabolic dysfunction-associated steatotic liver disease (MASLD) Semaglutide 37 and tirzepatide 22 were the only two OMM assessed in patients with MASLD. Tirzepatide resulted in a greater effect on TBWL% versus semaglutide in those patients. Tirzepatide, but not semaglutide, was capable of reducing AST, ALT, and liver stiffness levels and it was associated with a significantly higher rate of MASH remission and a decrease of at least 1 stage of liver fibrosis. Semaglutide and tirzepatide were both associated with a greater reduction of liver fat content in comparison with placebo (Table 2 and Figs. 40S and 41S). The GRADE evaluation of the evidence retrieved for the primary endpoint (diabetes remission, Table S3) was rated as “high” and “low” for tirzepatide and semaglutide, respectively (Table S9). 7) Obstructive sleep apnea syndrome (OSAS) One trial with tirzepatide enrolled patients living with obesity and OSAS 36 , reporting a reduction of the AHI (i.e., the number of apneas and hypopneas during an hour of sleep) and a higher percent reduction of AHI (Table 2 and Fig. 42S, Panel A and B). The GRADE evaluation of the evidence retrieved for the primary endpoint (reduction of AHI episodes, Table S3) was rated as “moderate” for tirzepatide (Table S9). 8) Knee osteoarthritis (KOA) Semaglutide 44 and liraglutide 26 were assessed in patients with obesity and KOA. Semaglutide, but not liraglutide 26 , was capable of reducing knee pain and ameliorating physical function assessed through the WOMAC scale (Table 2 and Fig. 43S). The GRADE evaluation of the evidence retrieved for the primary endpoint (reduction of knee pain, Table S3) was rated as “moderate” for semaglutide (Table S9) and “low” for liraglutide. DISCUSSION Through this systematic review and meta-analysis, we aimed to investigate the efficacy of different OMMs by analyzing available evidence from clinical trials across different patient categories and ORC. The efficacy on TBWL of currently available OMM is widely heterogeneous, with tirzepatide, semaglutide and, to a lesser extent, P/T showing a greater efficacy than other OMM. These differences in % TBWL were also evident in the proportion of patients reaching pre-defined targets of weight loss (e.g., 5%, 10%, etc., of initial body weight). The results of different OMMs on waist circumference and BMI are consistent with those for TBWL. Several patient-related factors can affect the amount of weight lost with each treatment. It is plausible that patients with a higher body weight at baseline experience a greater weight loss with treatment, as already reported in particular for MBS 45 . Differences in mean baseline BMI of patients enrolled in trials with different OMMs should be considered in the interpretation of the results of the present NMA. To address this possibility, we performed a subgroup analysis of trials, which enrolled patients in different BMI classes. Notably, few data (only with semaglutide) were available for patients with BMI over 40 kg/m 2 , and none could be retrieved for those with BMI 27–30 kg/m 2 . The large majority of data were collected in patients with BMI between 35.0 and 39.9 kg/m 2 ; in this category, differences in TBWL were similar to those observed in the whole sample. However, due to the paucity of data, observed differences in efficacy cannot be generalized to patients affected by overweight (i.e., with BMI 27–30 kg/m 2 ) or to those with a BMI ≥ 40 kg/m 2 . Most trials included in the analysis were designed with TBWL as the primary endpoint. However, there were some studies which were designed for other purposes, e.g., prevention of cardiovascular disease 14 or T2D 46 – 56 . The results on TBWL after the exclusion of trials that did not have TBWL as primary endpoint were comparable to the primary analysis, strengthening the reliability of comparisons. The presence of T2D is a negative moderator of the effects of some treatments, such as MBS, on body weight reduction 45 ; however, scarce evidence is available for OMMs. The present NMA suggests that patients with T2D experience less TBWL than those without T2D; this could be partly due to differences in baseline BMI and age, since patients with T2D enrolled in trials on obesity show, on average, a lower BMI and a higher age than patients without T2D. In addition, some of the patients with T2D enrolled in clinical trials may have a relevant glycosuria. The improvement of glucose control, directly determined by the medication (as in the case of GLP-1 receptor and dual GLP-1/GIP receptor agonists) or consequent to weight loss, can reduce glycosuria, hampering weight loss. Moreover, background therapy, particularly some medications such as thiazolidinediones, sulfonylureas, and insulin, could negatively affect the efficacy of OMM in patients with T2D. In patients with T2D, when analyzed separately, semaglutide and tirzepatide were associated with a greater reduction of HbA1c and FPG in comparison with other agents, producing a T2D remission (discontinuing pharmacological treatment) in a relevant proportion of cases. In addition, semaglutide and tirzepatide appeared to be more effective than other medications in preventing incident T2D in patients with pre-diabetes. This is not surprising, considering that tirzepatide and semaglutide evoked more pronounced TBWL and also have glucose-lowering effects by slowing gastric emptying, stimulating insulin secretion, and inhibiting glucagon secretion in a glucose-dependent manner, independent of their effects on body weight 57 . As anticipated, all OMMs contributed to improvements in lipid profiles, with orlistat demonstrating a greater effect on total cholesterol reduction than other agents. This aligns with its known mechanism of action, which involves the inhibition of intestinal fat absorption, leading to a reduction in serum lipid levels 58 . Most OMMs induced a reduction in triglycerides, which appeared to be greater with OMMs producing a greater weight loss, as expected 59 . Consistent with prior literature 60 , OMMs inducing weight loss also improved blood pressure, with the notable exception of N/B, which was associated with an increase in systolic blood pressure. This is a well-known side effect of N/B, and it is contra-indicated in patients with uncontrolled hypertension 61 . Weight loss generally induces a reduction in cardiovascular risk; so far, this effect has been clearly demonstrated in cardiovascular outcome trials specifically designed in patients with obesity only for semaglutide; while N/B did not show significant cardiovascular benefits. For tirzepatide, CVOTs are still not published. Hospitalizations for HF are reduced for both semaglutide and tirzepatide, highlighting their potential role in managing patients with concomitant heart failure. Cardiovascular mortality was significantly reduced with semaglutide and N/B, whereas the impact of tirzepatide cannot yet be established, as CVOTs are currently being analyzed. Weight reduction has long been considered a cornerstone in the management of OSAS and KOA. Tirzepatide produces a significant reduction in the AHI, reinforcing its potential role in OSAS management. Similarly, semaglutide demonstrated efficacy in reducing knee pain and improving physical function in patients with KOA. Although those benefits have been demonstrated only for specific OMMs (i.e., tirzepatide for OSAS and semaglutide for KOA), it is plausible that these effects are largely driven by weight reduction, rather than by unique pharmacodynamic properties of each molecule 62 , 63 . Despite their critical role in clinical practice, QoL and mental health have been infrequently studied in clinical trials, limiting the strength of conclusions regarding the impact of OMMs on these outcomes. In the few trials that assessed QoL, semaglutide and N/B determined marginal improvements. Future studies should prioritize the inclusion of QoL assessments to better understand the real-world impact of these treatments. Importantly, there were no significant concerns regarding suicide risk or major depressive events across the included trials. This finding is reassuring, given prior concerns regarding potential psychiatric adverse effects of weight-loss pharmacotherapies 64 . All OMMs demonstrated a generally favorable safety profile, but there were differences in SAE rates across interventions. SAEs were not significantly increased with any OMM, except for N/B, which showed a higher SAE rate compared to placebo. However, the long-term safety of these medications, including their potential associations with cancer risk 65 and other uncommon events, warrants further investigation. Despite the robustness of the present NMA, several limitations should be acknowledged. Heterogeneity in study populations, with variability in baseline BMI, age, and ORC among trial participants, may influence treatment effects. Notably, limited data were available for people with BMI ≥ 40 kg/m², the elderly, adolescents, and people with overweight (BMI ≥ 25 and < 30 kg/m²). Most trials were placebo-controlled, limiting the number of head-to-head comparisons that could be performed. In addition, the varying intensity of lifestyle interventions in the placebo groups of the different trials may further influence the results for comparative purposes. Furthermore, many trials lacked comprehensive reporting for key outcomes such as body composition changes, long-term safety, lifestyle interventions, and metabolic effects beyond glycemic control. Data on weight maintenance, metabolic effects, and SAEs longer than 2 years remain scarce, limiting insights into the durability of treatment benefits. Another relevant limitation of this NMA is the potential for inconsistency. NMAs integrate evidence from multiple trials by assuming that the relative effect of a given intervention is consistent across all included studies. This requires homogeneity in study design and participant characteristics, which may have not always been met. Although no significant inconsistency was detected in the primary analyses (H values < 3), differences in trial populations and methodologies should be considered when interpreting results. Disparities exist in the regulatory approval and availability of OMMs across different countries 66 – 68 . For instance, whilst phentermine is an approved pharmacological agent in some countries, it is not-approved by the regulatory authorities in others. These regulatory inconsistencies raise equity concerns, as access to effective obesity pharmacotherapy remains variable across populations. Addressing these disparities is crucial to ensuring equitable management opportunities for people with obesity worldwide. Conclusion This network meta-analysis reinforces the need to tailor obesity pharmacotherapy to the severity and type of ORCs, as certain medications demonstrate more pronounced effects on body weight and/or specific comorbid conditions compared to others. Overall, most OMMs are effective and safe for promoting total body weight loss and improving ORC. However, the impact of OMMs on specific complications still requires further investigation, and the information already published in 2025 reflects a rapidly evolving field that will need ongoing updates. Table 3 – Effects of OMM on endpoint Total Body Weight Loss (TBWL%) for different baseline BMI categories. Endpoint TBWL% BMI (kg/m 2 ) < 30 30-34.9 35.0-39.9 ≥ 40* Orlistat - 2.4 3.2 - Naltr/Bupr. - - 4.8 - Liraglutide - 5.0 4.3 - Phen/Topir. - - 8.6 9.3 Semaglutide - 9.4 10.2 10.6 Tirzepatide - 19.5 16.1 - *Data derived from traditional meta-analysis versus placebo; BMI: Body Mass Index. Naltr./Bupr. : Naltrexone/Bupropione; Phen./Topir. : Phentermine/Topiramate. Table 4 – Effects of different OMM on body weight parameters (placebo-subtracted effect) in RCTs specifically designed for body weight reduction. Declarations Ethical Approval: Not applicable. Competing interests: Not applicable. Data availability statement: in Supplementary Information there are all the references linked to dataset. Role of the funding source None. Acknowledgement section The authors wish to thank Edoardo Mannucci and Benedetta Ragghianti for their external support in collecting data and revising the final draft of the present manuscript Declaration of Interests Barbara McGowan has received speaker and/or advisory fees from Novo Nordisk, Eli-Lilly, Astra Zeneca, Janssen, Pfizer, MSD and a research grant from Novo Nordisk. BM is a shareholder of Reset Health. Andreea Ciudin has received speaking fees from Astra Zeneca, Boehringer-Ingelheim, Eli-Lilly, Novo Nordisk, Sanofi, Menarini and research grants from Eli Lilly, NovoNordisk and Menarini. Member of the DMC of Boehringer Ingelheim. Jennifer L. Baker has received a consulting fee and is an advisory board member for Novo Nordisk A/S with fees paid to her institution. Luca Busetto (LB) has received payment of honoraria from Eli Lilly, Novo Nordisk, Boehringer Ingelheim, Pfizer, Bruno Farmaceutici, Regeneron, Rythm Pharmaceuticals and Pronokal as speaker and/or member of advisory boards. Dror Dicker has received speaker and advisory board fees from Boehringer-Ingelheim, Eli-Lilly, Novo Nordisk, Astra Zeneca and research grants from Eli Lilly, NovoNordisk and Boehringer Ingelheim. Gema Frühbeck has received payment of honoraria from Eli Lilly, Novo Nordisk, Regeneron and Astra Zeneca as speaker and/or member of advisory boards, and payment of honoraria as member of the OPEN Spain Initiative. Gijs Goossens has no conflicts of interest to declare. Borja Martinez-Tellez has received grants from the EASO New Clinical Investigator Award 2024 and the EFSD Rising Star 2024, both supported by the Novo Nordisk Foundation. Matteo Monami has received speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Bristol Myers Squibb. Paolo Sbraccia received payment of honoraria and consulting fees from Boehringer Ingelheim, Chiesi, Novo Nordisk, Eli Lilly, Pfizer, and Roche as a member of advisory boards. Euan Woodward has no conflicts of interest to declare. Volkan Yumuk was engaged in advisory boards and lectures with: Novo Nordisk, Eli Lilly, Rhythm, Regeneron. Authors' contributions All the authors approved the final version of this manuscript. Dr. BM is the person who takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript 2 Authors involvement in each of the following points: 1. Design: BMG, AC, LB, MM, DD, GF, GHG, PS, VY 2. Data collection: MM, BMT 3. Analysis: MM 4. 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Supplementary Files SupportingMaterialsEASO14042025.docx European Association for the Study of Obesity (EASO) grade-based framework on Pharmacological Algorithm for the treatment of obesity and its complications Table1and2.docx Cite Share Download PDF Status: Published Journal Publication published 02 Oct, 2025 Read the published version in Nature Medicine → Version 1 posted 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-6449183","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":444519110,"identity":"2a35bb88-bb3e-4392-8d37-75abefdd10a6","order_by":0,"name":"Andreea Ciudin","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0001-5622-0203","institution":"VALL HEBRON UNIVERSITY HOSPITAL","correspondingAuthor":true,"prefix":"","firstName":"Andreea","middleName":"","lastName":"Ciudin","suffix":""},{"id":444519111,"identity":"f4492a87-0e56-4e31-bd9d-9f159ae0ad57","order_by":1,"name":"Barbara McGowan","email":"","orcid":"","institution":"Department of Endocrinology and Diabetes, Guys \u0026 St Thomas ‘s Hospital NHS Trust","correspondingAuthor":false,"prefix":"","firstName":"Barbara","middleName":"","lastName":"McGowan","suffix":""},{"id":444519112,"identity":"102d6e14-bfdb-4e0f-bd55-5d8e6fdf4e29","order_by":2,"name":"Andreea Ciudin","email":"","orcid":"","institution":"VALL HEBRON UNIVERSITY HOSPITAL","correspondingAuthor":false,"prefix":"","firstName":"Andreea","middleName":"","lastName":"Ciudin","suffix":""},{"id":444519113,"identity":"f8c93d56-5788-4947-8130-3215a1f98f30","order_by":3,"name":"Jennifer Baker","email":"","orcid":"https://orcid.org/0000-0002-9649-6615","institution":"Center for Clinical Research and Prevention, Copenhagen University Hospital-Bispebjerg and Frederiksberg","correspondingAuthor":false,"prefix":"","firstName":"Jennifer","middleName":"","lastName":"Baker","suffix":""},{"id":444519114,"identity":"980364a4-e552-402a-a2e6-ff1d93683199","order_by":4,"name":"Luca Busetto","email":"","orcid":"https://orcid.org/0000-0003-4883-8980","institution":"University of Padova","correspondingAuthor":false,"prefix":"","firstName":"Luca","middleName":"","lastName":"Busetto","suffix":""},{"id":444519115,"identity":"763d5f19-12f0-4a4c-a1ae-98a8a5274206","order_by":5,"name":"Dror Dicker","email":"","orcid":"","institution":"Internal Medicine D, Hasharon Hospital-Rabin Medical Center, Petach Tikva","correspondingAuthor":false,"prefix":"","firstName":"Dror","middleName":"","lastName":"Dicker","suffix":""},{"id":444519116,"identity":"5e9ed2f9-9d40-4e99-be10-336b095aee36","order_by":6,"name":"Gema Frühbeck","email":"","orcid":"https://orcid.org/0000-0002-8305-7154","institution":"Clinica Universidad de Navarra","correspondingAuthor":false,"prefix":"","firstName":"Gema","middleName":"","lastName":"Frühbeck","suffix":""},{"id":444519117,"identity":"3b8b9af0-63d3-4641-81a7-b953dd381325","order_by":7,"name":"Gijs Goossens","email":"","orcid":"https://orcid.org/0000-0002-2092-3019","institution":"Maastricht University Medical Center+","correspondingAuthor":false,"prefix":"","firstName":"Gijs","middleName":"","lastName":"Goossens","suffix":""},{"id":444519118,"identity":"dc728b75-78e7-48d9-be73-173d04415e0e","order_by":8,"name":"Matteo Monami","email":"","orcid":"","institution":"Diabetes Unit; Careggi Teaching Hospital","correspondingAuthor":false,"prefix":"","firstName":"Matteo","middleName":"","lastName":"Monami","suffix":""},{"id":444519119,"identity":"3fe04b60-50f1-4862-af14-b6b74b3913eb","order_by":9,"name":"Paolo Sbraccia","email":"","orcid":"","institution":"Department of Systems Medicine, University of Rome Tor Vergata","correspondingAuthor":false,"prefix":"","firstName":"Paolo","middleName":"","lastName":"Sbraccia","suffix":""},{"id":444519120,"identity":"4330981d-cc10-4954-ad5a-6c01ff1c799f","order_by":10,"name":"Borja Martinez Tellez","email":"","orcid":"","institution":"Department of Nursing, Physiotherapy and Medicine, CIBIS Research Center, University of Almería, Almería, Spain. CIBEROBN, Instituto de Salud Carlos III","correspondingAuthor":false,"prefix":"","firstName":"Borja","middleName":"Martinez","lastName":"Tellez","suffix":""},{"id":444519121,"identity":"cbc457a7-8179-40a6-8942-055d34692173","order_by":11,"name":"Euan Woodward","email":"","orcid":"","institution":"European Association for the Study of Obesity","correspondingAuthor":false,"prefix":"","firstName":"Euan","middleName":"","lastName":"Woodward","suffix":""},{"id":444519122,"identity":"b549dbba-03b7-45d3-a6db-c3ddcd4ba930","order_by":12,"name":"Volkan Yumuk","email":"","orcid":"","institution":"Division of Endocrinology, Metabolism and Diabetes, Istanbul University-Cerrahpaşa, Cerrahpaşa Medical Faculty,","correspondingAuthor":false,"prefix":"","firstName":"Volkan","middleName":"","lastName":"Yumuk","suffix":""}],"badges":[],"createdAt":"2025-04-14 21:35:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6449183/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6449183/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41591-025-03978-z","type":"published","date":"2025-10-02T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":81176654,"identity":"4857e2bc-9491-458e-a12a-6b9d2fcdb242","added_by":"auto","created_at":"2025-04-23 06:25:19","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":239121,"visible":true,"origin":"","legend":"\u003cp\u003eNetwork plots for trials reporting information on TBWL% at the endpoint (Panel A), 52 weeks (Panel B), and 53-104 weeks (Panel C).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6449183/v1/03e6289844bd093a84e2d2f0.png"},{"id":81177726,"identity":"6923f614-39df-4300-a4f2-2486516b246b","added_by":"auto","created_at":"2025-04-23 06:41:19","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":259470,"visible":true,"origin":"","legend":"\u003cp\u003eNetwork forest plots showing the effects of each OMM on TBWL% at the endpoint (Panel A), 52 weeks (Panel B), 53-104 weeks (Panel C).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6449183/v1/65bd1d6c3c7f92b6ca1772e5.png"},{"id":92696387,"identity":"19f22b0e-25b2-47e4-bf88-ba00a5577f1c","added_by":"auto","created_at":"2025-10-03 07:07:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1626268,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6449183/v1/1d675fb3-b1d0-429b-bc88-09f1d1b99a6b.pdf"},{"id":81177013,"identity":"7415afa5-a87b-4353-9b86-121606eb9705","added_by":"auto","created_at":"2025-04-23 06:33:19","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":2515703,"visible":true,"origin":"","legend":"European Association for the Study of Obesity (EASO) grade-based framework on Pharmacological Algorithm for the treatment of obesity and its complications","description":"","filename":"SupportingMaterialsEASO14042025.docx","url":"https://assets-eu.researchsquare.com/files/rs-6449183/v1/471713cbc1ca11b70af14b6b.docx"},{"id":81176655,"identity":"0247ec0a-90f4-470b-be2e-9f47fc2725de","added_by":"auto","created_at":"2025-04-23 06:25:19","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":176100,"visible":true,"origin":"","legend":"","description":"","filename":"Table1and2.docx","url":"https://assets-eu.researchsquare.com/files/rs-6449183/v1/0284cce91a6a13b3eee0c600.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Pharmacological management of obesity in adults: a systematic review and meta-analysis of randomized controlled trials to evaluate the efficacy and safety of obesity management medications","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eThe prevalence of overweight and obesity is either increasing or at a level that is too high in many countries worldwide, leading to a rise in metabolic and cardiovascular diseases, cancer, and overall mortality\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Considering the high prevalence of obesity and its harmful impact on health\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e, its management represents a complex medical and economic\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e challenge for all healthcare systems. Currently, lifestyle intervention is the first-line treatment for people with obesity. However, its mid- and long-term effects and adherence is limited\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eObesity is an adipose-based chronic disease driven by biological mechanisms, resulting in dysregulation and/or excess accumulation of adipose tissue\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. The biology of obesity includes genetic predisposition, neurohormonal signaling disruptions (particularly in the hypothalamus), and alterations in appetite-regulating hormones\u003csup\u003e\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Furthermore, the body defends against fat loss through mechanisms including reduced resting energy expenditure and increased hunger, making long-term weight maintenance challenging. As a result, lifestyle interventions alone\u0026mdash;such as diet and exercise\u0026mdash;are often insufficient, and effective management typically requires a combination of strategies to address the underlying biology of obesity. Current guidelines recommend that, particularly for high-risk people with severe obesity or obesity-related complications (ORC), lifestyle programs can be combined with obesity management medications (OMMs) or metabolic bariatric surgery (MBS)\u003csup\u003e\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eRecent advances in the biology of obesity have led to the development of novel medications, providing healthcare professionals with a broader range of therapeutic options\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Due to regulatory requirements, newer medications are supported by clinical trials on substantial numbers of patients, often including studies on longer-term cardiovascular outcomes\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. However, the availability of head-to-head comparisons between different OMMs in randomized controlled trials (RCTs) is still limited\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e, which makes assessment of differences in efficacy and safety across available molecules is challenging. The method of network meta-analysis (NMA), which provides indirect comparisons of efficacy and safety, can overcome this challenge. Several NMAs on different therapeutic options for overweight and obesity have been published in the last few years\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e, but they did not include more recently available OMMs, such as tirzepatide\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e, or included medications not approved for the treatment of overweight/obesity (e.g., metformin, SGLT2 inhibitors, or GLP-1 agonists such as dulaglutide, etc.)\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe European Association for the Study of Obesity (EASO) has developed the first GRADE-based (Grading of Recommendations Assessment, Development and Evaluation) treatment algorithm for the pharmacological management of obesity, as outlined in the 2024 EASO framework\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. This algorithm was created using the findings of the present network meta-analysis (NMA), which aims to provide healthcare professionals involved in obesity care with a comprehensive overview based on published data on the efficacy and safety of all obesity management medications (OMMs) available in Europe until January 31, 2025.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003eThis NMA is reported following the criteria of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003eS).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy search and selection\u003c/h2\u003e \u003cp\u003eThe protocol for this meta-analysis and NMA was published on the PROSPERO website (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.crd.york.ac.uk/prospero/#recordDetails\u003c/span\u003e\u003cspan address=\"https://www.crd.york.ac.uk/prospero/#recordDetails\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e; registration number: CRD42024625338) and in a previous article\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. The present analysis included all placebo-or active- RCTs that enrolled adults (\u0026ge;\u0026thinsp;18 years) with obesity (body mass index; BMI\u0026thinsp;\u0026ge;\u0026thinsp;30 kg/m\u003csup\u003e2\u003c/sup\u003e) or overweight (BMI\u0026thinsp;\u0026gt;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e), with a treatment duration of at least 48 weeks, which compared OMMs with the specific indication of obesity treatment with either placebo or other OMM. Further, the RCTs needed to be performed on OMMs available in at least one EASO member country as of January 31, 2025. The OMMs and doses included were: orlistat (360 mg), phentermine plus topiramate (P/T, 15/92 mg), naltrexone plus bupropion (N/B, 32/360 mg), liraglutide (3.0 mg), semaglutide (2.4 mg), and tirzepatide (10\u0026ndash;15 mg).\u003c/p\u003e \u003cp\u003eA Medline and Embase search was performed up to January 31, 2025; detailed information on the search strategy and keywords used is reported in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003eS of the Supplementary Materials. Duplicate records were removed with EndNote X9 (Clarivate Analytics, Philadelphia, PA, USA).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData extraction\u003c/h3\u003e\n\u003cp\u003eInformation on the baseline characteristics of the samples enrolled (age, gender, proportion of patients with T2D, baseline BMI, total body weight loss (TBWL%), waist circumference, body composition, proportion of patients achieving at least 5%, 10%, 15%, 20%, and 25% body weight reduction, remission or improvement/resolution of ORC, serious adverse events (SAE), mortality, major adverse cardiovascular events (MACE), fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), lipid profile, estimated glomerular filtration rate (eGFR), creatinine, albuminuria, mental health parameters, and quality of life (QoL). Two authors performed data extraction independently (B.R., E.M), and conflicts were resolved by a third investigator (M.M.).\u003c/p\u003e\n\u003ch3\u003eQuality assessment\u003c/h3\u003e\n\u003cp\u003eThe risk of bias was assessed using the Cochrane recommended tool to determine the risk of bias in RCTs\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. The risk of bias was described and evaluated in seven specific domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases. The results of these domains were graded as low, high, or uncertain risk of bias. Two researchers (B.R. and E.M.) independently assessed the risk of bias in individual studies, with discrepancies resolved by a third researcher (M.M.).\u003c/p\u003e \u003cp\u003e\u003cstrong\u003eData analysis\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eThe principal endpoint was TBWL% at the end of treatment; secondary endpoints were:\u003c/p\u003e\n\u003cp\u003ea) TBWL% at 52 weeks, 53-104 weeks, 105-156 weeks, \u0026gt;156 weeks.\u003c/p\u003e\n\u003cp\u003eb) Change in endpoint BMI and waist circumference.\u003c/p\u003e\n\u003cp\u003ec) Change in total Fat Mass (FM), Subcutaneous Fat Mass (SFM) and Visceral Fat Mass (VFM).\u003c/p\u003e\n\u003cp\u003ed) Change in Fat-Free Mass (FFM).\u003c/p\u003e\n\u003cp\u003ee) The proportion of patients achieving at least 5, 10, 15, 20%, and 25% body weight reduction\u003c/p\u003e\n\u003cp\u003ef) Type 2 Diabetes (T2D), Hypertension (HTN), and Dyslipidemia (DL) remission. Type 2 diabetes remission was defined as HbA1c\u0026lt; 6.5% at endpoint.\u003c/p\u003e\n\u003cp\u003eg) MASH (metabolic dysfunction\u0026ndash;associated steatohepatitis) resolution (defined as no steatotic liver disease without worsening of fibrosis), improvement of liver fibrosis (defined as a decrease of at least one fibrosis stage without worsening of MASH\u003csup\u003e22\u003c/sup\u003e). Obstructive Sleep Apnea Syndrome (OSAS) resolution (defined as Apnea-Hypopnea Index (AHI) \u0026lt;5 or AHI of 5 to 14), and improvement of Knee Osteoarthritis (KOA) (improvement in pain/physical functioning items of any validated scale assessing quality of life in patients with KOA).\u003c/p\u003e\n\u003cp\u003eh) Reduction of hospital admission for heart failure (HHF), considering only studies in which these events were formally adjudicated.\u003c/p\u003e\n\u003cp\u003ei) Any SAE.\u003c/p\u003e\n\u003cp\u003ej) All-cause mortality.\u003c/p\u003e\n\u003cp\u003ek) MACE (composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular mortality), considering only studies in which these events were formally adjudicated.\u003c/p\u003e\n\u003cp\u003el) Endpoint FPG, HbA1c, lipid profile, eGFR, creatinine, and albuminuria.\u003c/p\u003e\n\u003cp\u003em) Change in mental health parameters.\u003c/p\u003e\n\u003cp\u003en) Quality of Life (QoL).\u003c/p\u003e\n\u003cp\u003eAll the endpoints, except point a), were collected at the end of the trials.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMean and 95% confidence intervals (95% CI) for continuous variables and Mantel-Haenzel Odds Ratio [MH-OR] for categorical variables were calculated, using random effect models. When data were reported as least-squares mean and standard error (SE), the standard deviation (SD) was obtained for each group using the following formula: SD= \u0026radic;(number of patients)*(CI upper limit \u0026ndash; CI lower limit)/3.92 and SD= \u0026radic;(number of patients)*SE, respectively (http://handbook-5-1.cochrane.org/chapter_7/7_7_3_2_obtaining_standard_deviations_from_standard_errors_and.htm).\u003c/p\u003e\n\u003cp\u003ePrespecified subgroup analyses were performed for the following baseline variables: different OMMs, BMI categories (mean BMI at the enrolment \u0026lt;30, 30-34.9, 35-39.9, and \u0026gt;40 kg/m\u003csup\u003e2\u003c/sup\u003e), T2D (RCT enrolling at least 75% of patients with diabetes), prediabetes\u003csup\u003e23\u003c/sup\u003e, previous established cardiovascular disease (CVD), heart failure (HF), KOA, MASLD, and OSAS. A further subgroup analysis was performed only for body weight parameters (i.e., TBWL%, waist circumference, BMI, and proportion of patients achieving at least 5, 10, 15, 20, and 25% of body weight reduction) in RCTs specifically designed for body weight reduction.\u003c/p\u003e\n\u003cp\u003eTable 3S reports the principal endpoints (together with the others considered critical) for all these subpopulations of patients with obesity.\u003c/p\u003e\n\u003cp\u003eTraditional meta-analyses were performed for the primary endpoint and the other outcomes if they were reported in less than 10 RCTs. Heterogeneity was assessed by using I\u003csup\u003e2\u003c/sup\u003e statistic. Random-effect models were applied for all the analyses reported above.\u003c/p\u003e\n\u003cp\u003eWe performed a NMA\u003csup\u003e24\u003c/sup\u003e for all the outcomes listed above to examine differences across individual OMMs concerning their effects on primary and secondary endpoints. These analyses allow indirect comparisons when direct trials are unavailable, using differences from common comparators, and then combining direct and indirect comparisons for a final estimate of effects. The reference category was placebo. We performed NMA within a pairwise modeling (GPM) framework using the software program MetaXL (www.epigear.com). H values were calculated to test consistency between direct and indirect evidence; H\u0026lt;3 indicates minimal inconsistency of treatment effects.\u003c/p\u003e\n\u003cp\u003eAll other analyses were performed using Review Manager (RevMan), Version 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014).\u003c/p\u003e\n\u003cp\u003eThe GRADE methodology\u003csup\u003e11\u003c/sup\u003e was used to assess the quality of the body of retrieved evidence for the principal endpoint, with the GRADEpro GDT software (GRADEpro Guideline Development Tool. McMaster University, 2015. Available from gradepro.org).\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eRetrieved trials\u003c/h2\u003e \u003cp\u003eFigure 1S of Supporting Materials reports the trial flow summary showing the results of the search of Medline and Embase databases. Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003eS of Supplementary Materials reports which trials were excluded (n\u0026thinsp;=\u0026thinsp;7) after reading the full text. Out of 55 clinical trials, performed with orlistat (n\u0026thinsp;=\u0026thinsp;21), semaglutide (n\u0026thinsp;=\u0026thinsp;12), liraglutide (n\u0026thinsp;=\u0026thinsp;9), tirzepatide (n\u0026thinsp;=\u0026thinsp;6), N/B (n\u0026thinsp;=\u0026thinsp;5), and P/T (n\u0026thinsp;=\u0026thinsp;2), enrolling 62,861 patients (33,986 and 28,804 with active compound and placebo, respectively) were analyzed. All RCTs were placebo-controlled studies, except for one trial that reported multiple comparisons (i.e., liraglutide versus placebo or orlistat); therefore the overall number of available comparisons was 56. The main characteristics of the included RCTs are reported in Table\u0026nbsp;5S of the Supporting Materials. No studies reported a mean baseline BMI\u0026thinsp;\u0026lt;\u0026thinsp;30 kg/m\u003csup\u003e2\u003c/sup\u003e; one trial disclosed subgroup analyses for the primary endpoint across different BMI categories\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe quality of studies was heterogeneous (Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003eS and 3S of Supporting Materials). Most of the included RCTs were double-blind (66%), with few trials inadequately reporting attrition and/or description of allocation or blinding of assessors (29%).\u003c/p\u003e \u003cp\u003eOut of 56 treatment arms, 55 comparisons were performed versus placebo. All, except five\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan additionalcitationids=\"CR27 CR28\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e, reported information on TBWL% at the endpoint. Only one head-to-head comparison\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e between different OMMs was identified (i.e., liraglutide vs. orlistat), showing a greater efficacy for liraglutide than for orlistat (WMD: 3.80 [0.73, 6.87]%, p\u0026thinsp;=\u0026thinsp;0.020).\u003c/p\u003e \u003cp\u003e \u003cb\u003eNetwork meta-analysis\u003c/b\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003e1) Effects on body weight\u003c/h3\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e1.1 TBWL% at different time points\u003c/h2\u003e \u003cp\u003eFigure 1 reports the number of available RCTs for each comparison, while Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e show the efficacy results with respect to TBWL% at the end of the different time points (52, 104, \u0026gt;\u0026thinsp;156 weeks, and at end of the study), based on the NMA. At the primary endpoint (n\u0026thinsp;=\u0026thinsp;50 comparisons, with no evidence of inconsistency; H\u0026thinsp;=\u0026thinsp;1.00), all OMM yielded a statistically significant greater TBWL% in comparison with placebo. The estimated TBWL% was greater than 10% only for semaglutide and tirzepatide (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e, panel A). Details of direct and indirect estimates are reported in Table\u0026nbsp;6S. A visual analysis of funnel plots did not suggest publication bias (Fig.\u0026nbsp;4S).\u003c/p\u003e \u003cp\u003eAt 52 weeks (n\u0026thinsp;=\u0026thinsp;50 comparisons, with evidence of inconsistency; H\u0026thinsp;=\u0026thinsp;4.01), all treatments showed a significantly greater TBWL% versus placebo, except for orlistat (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Panel B). Similar to the endpoint analyses, only semaglutide and tirzepatide achieved a TBWL% of at least 10% (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Panel B). Details of direct and indirect estimates are reported in Table\u0026nbsp;7S.\u003c/p\u003e \u003cp\u003eA limited number of comparisons were possible at 53 to 104 weeks (n\u0026thinsp;=\u0026thinsp;13; H\u0026thinsp;=\u0026thinsp;1.00; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e panel C and Table\u0026nbsp;8S), 105\u0026ndash;156 weeks (n\u0026thinsp;=\u0026thinsp;3, Fig.\u0026nbsp;5S) and \u0026gt;\u0026thinsp;156 weeks (one trial\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e with orlistat reporting a 3% TBWL in comparison with placebo, and one subgroup analysis\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e of a trial with tirzepatide\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e reporting 19.3% TBWL). For all assessed treatments, the estimated efficacy at the endpoint was similar to that observed at 52 weeks and 104 weeks.\u003c/p\u003e \u003cp\u003e \u003cem\u003e1.2 Waist circumference, BMI, and proportion of patients achieving at least 5%, 10%, 15%, 20%, and 25% of TBWL\u003c/em\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Figs.\u0026nbsp;6S and 7S report results of the effects of each OMM on endpoint waist circumference and BMI (% reduction from baseline). Tirzepatide and semaglutide were associated with a greater reduction of both waist circumference and BMI. Trials on P/T did not report information on these two endpoints and thus were not included in these analyses.\u003c/p\u003e \u003cp\u003eThe proportion of patients achieving different thresholds of TBWL% are reported in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Figs.\u0026nbsp;8S and 9S. Patients treated with OMMs, except for orlistat, were more likely to achieve a TBWL of at least 5% in comparison with placebo. A higher degree of TBWL (\u0026gt;\u0026thinsp;20%) was observed only with semaglutide and tirzepatide and, to a lesser extent, with liraglutide. Only tirzepatide was associated with a greater proportion of patients achieving at least 25% TBWL reduction (Fig.\u0026nbsp;9S, Panel E). Five trials\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan additionalcitationids=\"CR33 CR34\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e reported results on body composition parameters assessed using heterogeneous methods (often in a smaller subgroup of included patients). Two studies on semaglutide\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e did not report any information about dispersion measurements and, therefore were not included in any formal analyses. Semaglutide showed a greater reduction of total\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e and regional visceral fat mass\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e,\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e and a greater increase in total lean body mass\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e in comparison with placebo. Tirzepatide was associated with a greater reduction of total body fat mass and a significantly lower reduction in total fat-free mass\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e; similar results, despite to a lesser extent, were observed with liraglutide\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWhen subdividing trials by baseline BMI (\u0026lt;\u0026thinsp;30; 30-34.9; 35-39.9; \u0026ge;40.0 kg/m\u003csup\u003e2\u003c/sup\u003e; Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), no RCTs on OMMs reported results for patients with overweight; only two OMMs (semaglutide and tirzepatide) provided data for class III obesity (BMI\u0026thinsp;\u0026ge;\u0026thinsp;40.0 kg/m\u003csup\u003e2\u003c/sup\u003e; Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Figs.\u0026nbsp;44S-46S). The majority of information on the effects of each included OMM was available for the class II obesity (35-39.9 kg/m\u003csup\u003e2\u003c/sup\u003e) category, which showed the highest body weight reduction for tirzepatide and semaglutide (TBWL% \u0026gt;10%). A further post-hoc subgroup analysis was performed for RCTs specifically designed for body weight reduction. The results of these analyses, after excluding RCTs\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan additionalcitationids=\"CR37\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e with a primary endpoint other than body weight reduction, are reported in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e and Figs.\u0026nbsp;10S-13S. Results from these analyses were similar to those of the primary endpoint analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e2) Effects on glycemic control, blood pressure and lipid profile\u003c/h2\u003e \u003cp\u003eData were obtained considering all RCTs reporting data on each metabolic endpoint, irrespective of the proportion of patients with T2D or prediabetes. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Figs.\u0026nbsp;14-21S report results for metabolic parameters (n\u0026thinsp;=\u0026thinsp;24, 32, 29, 35, and 32 RCTs for HbA1c, FPG, total and HDL-cholesterol, and triglycerides, respectively) and blood pressure (n\u0026thinsp;=\u0026thinsp;35 and 29 RCTs for systolic and diastolic blood pressure, respectively). Tirzepatide produced a significantly greater reduction in HbA1c in comparison with other OMMs, whereas liraglutide and semaglutide were associated with a greater reduction of FPG in contrast with the other OMMs (Figs.\u0026nbsp;14S and 15S). T2D remission was reported in a low number of RCTs (n\u0026thinsp;=\u0026thinsp;5) and, therefore, we performed traditional meta-analyses showing significant results for N/B, liraglutide, semaglutide, and tirzepatide (Fig.\u0026nbsp;16S and 17S). Eight trials reported data on incident T2D, showing a positive effect for liraglutide, P/T, and semaglutide, but not orlistat (Fig.\u0026nbsp;25S). Semaglutide and tirzepatide, but not liraglutide, were associated with a higher chance of restoring normoglycemia in patients with pre-existing glycemic alterations (Fig.\u0026nbsp;26S).\u003c/p\u003e \u003cp\u003eOrlistat was associated with the highest total cholesterol reduction, and statistically significant results versus placebo were also obtained for P/T and liraglutide. Tirzepatide, N/B, and liraglutide were associated with a greater increase of HDL-cholesterol values; semaglutide, P/T, and orlistat resulted in a significant reduction of triglyceride circulating levels (Figs.\u0026nbsp;18S and 19S). Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig.\u0026nbsp;20S show the effects of each OMM on blood pressure, with N/B associated with a significant increase in systolic, but not diastolic, blood pressure. All the other OMMs exerted significant favorable effects on systolic blood pressure and some (P/T, tirzepatide, and orlistat) on diastolic blood pressure.\u003c/p\u003e \u003cp\u003eOnly a few RCTs reported data on hypertension and dyslipidemia remission, with clinically inconsequential effects (Figs.\u0026nbsp;21S and 22S).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3) Effects on cardiovascular morbidity and mortality\u003c/h2\u003e \u003cp\u003eThirty-two, 36, and 7 RCTs reported information on (externally adjudicated) MACE, cardiovascular mortality, and HHF, respectively (Figs.\u0026nbsp;27S and 29S). Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Figs.\u0026nbsp;25S and 26S show results on these endpoints. Only semaglutide was associated with a significantly lower risk for MACE, with all OMMs reporting odds ratios below 1, except for PT (OR: 2.00 [0.18; 22.1], p\u0026thinsp;\u0026gt;\u0026thinsp;0.50; Fig.\u0026nbsp;28S, panel B). No information on cardiovascular mortality was reported for P/T. Semaglutide and N/B were associated with a lower risk for cardiovascular mortality (Fig.\u0026nbsp;28S, panel C). HHF was significantly reduced by tirzepatide (n\u0026thinsp;=\u0026thinsp;2 RCTs), whereas semaglutide (n\u0026thinsp;=\u0026thinsp;4 RCTs) showed a non-signifcant trend toward a reduction. Liraglutide reported zero events in both arms, and therefore, the overall risk was not estimable (Fig.\u0026nbsp;29S).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e4) Effects on quality of life and mental health\u003c/h2\u003e \u003cp\u003eOnly a few trials reported data on quality of life, using different scales (8, 2, 7, and 1 with IWQOL-Lite, SF-36 General Health, SF-36 Physical Role Functioning, SF-36 Physical Components, respectively). The paucity of data did not support a NMA, but only traditional meta-analyses (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig.\u0026nbsp;30S of Supplementary Materials). N/B and semaglutide were associated with an improvement of IWQOL versus placebo (Fig.\u0026nbsp;30S panel A). Only one active-controlled trial (liraglutide versus orlistat) reported data on IWQOL, showing better scores for liraglutide\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. No other significant differences were observed across the remaining scales, except for semaglutide, which showed improved scores in the Short Form-36 Physical Functioning domain (Fig.\u0026nbsp;30S, panel C).\u003c/p\u003e \u003cp\u003eSuicide attempts and major depression were reported as SAE (with no external adjudication) in a high number of RCTs (Fig.\u0026nbsp;31S, panel C and D). No significant association was observed between treatment with any OMM and the risk for either suicide attempt or depression, except for N/B, which was associated with a significantly lower risk of depression (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig.\u0026nbsp;32S, panel C and D). Few studies reported about anxiety (n\u0026thinsp;=\u0026thinsp;9), thus a NMA was not possible, and the standard meta-analysis did not show a significant association for any OMM (Fig.\u0026nbsp;30S).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e5) Safety outcomes\u003c/h2\u003e \u003cp\u003eResults on all-cause mortality are reported in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Figs.\u0026nbsp;27S and 28S. Semaglutide was associated with a lower risk of mortality; the other OMMs did not show any significant effect on this endpoint (Fig.\u0026nbsp;25S). SAEs (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Figs.\u0026nbsp;31S and 32S) were reported in most included studies, and no OMM was significantly associated with an increased risk of SAEs in comparison with placebo, except for N/B. The treatment discontinuation rate was similar to that observed in the placebo arms, with no significant between-group differences (Figs.\u0026nbsp;31S and 32S).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e6) GRADE evaluation for the primary endpoint\u003c/h2\u003e \u003cp\u003eThe evaluation of the quality of evidence for the primary endpoint (i.e., TBWL%) was rated as \u0026ldquo;high\u0026rdquo; (Table\u0026nbsp;9S) for each OMM.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eSubgroup analyses for patients\u0026rsquo; pre-existing conditions\u003c/h2\u003e \u003cp\u003eAs reported in a previously published article\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e, EASO identified several subgroups of patients with pre-existing comorbid conditions (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003eS of Supplementary Materials). In this section, we analyzed the effects of each OMM on several prespecified critical outcomes in specifically designed RCTs or in reported subgroups of patients affected by that comorbid condition\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003e1) Established CVD\u003c/h2\u003e \u003cp\u003eOnly two trials, one with semaglutide\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e and one with N/B\u003csup\u003e15\u003c/sup\u003e, were designed to explore the effects on cardiovascular safety in patients with obesity. Information on TBWL% was available only for semaglutide, with results similar to those obtained in non-cardiovascular outcome trials (8.7%; Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Semaglutide, but not N/B, was associated with a significantly lower risk of MACE and acute myocardial infarction in patients with established cardiovascular disease, whereas cardiovascular mortality was reduced by N/B but not by semaglutide. In contrast, both OMM reported a significantly lower risk for all-cause mortality compared to placebo (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe GRADE evaluation of the evidence retrieved for the primary endpoint (MACE, Table S3) was rated as \u0026ldquo;high\u0026rdquo; and \u0026ldquo;moderate\u0026rdquo; for semaglutide and NB, respectively (Table S9).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003e2) Hospitalization for heart failure (HHF)\u003c/h2\u003e \u003cp\u003eThree trials (two with semaglutide\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e,\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e and one with tirzepatide\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e) included patients with previously diagnosed HF. The effects of the two medications for TBWL% were not different from other non-cardiovascular outcome trials, despite a slightly less efficacy for tirzepatide (11.7 vs 16.5%; Figs.\u0026nbsp;35S and 36S). The risk of HHF was significantly reduced for both semaglutide and tirzepatide, with increased specific-disease quality of life questionnaires (KCCQ) scores and performances at 6-minute walking test. No relevant effects on all-cause and cardiovascular mortality were observed for the two medications (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e; Figs.\u0026nbsp;35 and 36S).\u003c/p\u003e \u003cp\u003eThe GRADE evaluation of the evidence retrieved for the primary endpoint (HHF, Table S3) was rated as \u0026ldquo;high\u0026rdquo; for both tirzepatide and semaglutide (Table S9).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003e4) Prediabetes\u003c/h2\u003e \u003cp\u003eTwo studies (one with liraglutide and one with semaglutide) were specifically designed for patients affected by overweight/obesity and prediabetes\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e, and two more studies (one with orlistat\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e and one with tirzepatide\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e) reported a longer-term analysis on a subgroup of patients with prediabetes. All those four OMMs (orlistat, liraglutide, semaglutide, and tirzepatide) are capable of effectively reducing TBWL%, HbA1c, and FPG in patients with prediabetes. Orlistat, liraglutide and tirzepatide, but not semaglutide, were associated with a significant reduction of incident diabetes. Normoglycemia restoration was more likely to be achieved in the interventional group for liraglutide, semaglutide, and tirzepatide, but not orlistat, in comparison with placebo (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, and Fig.\u0026nbsp;37S). The GRADE evaluation of the evidence retrieved for the primary endpoint (normoglycemia restoration, Table S3) was rated as \u0026ldquo;high\u0026rdquo; for all OMM reporting this outcome, except for orlistat (\u0026ldquo;low\u0026rdquo;; Table S9).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003e5) Type 2 diabetes\u003c/h2\u003e \u003cp\u003eEleven trials have been performed in patients with diabetes (Fig.\u0026nbsp;38S). Tirzepatide was associated with a greater effect on TBWL%; semaglutide, tirzepatide, and N/B were all associated with significant effects on HbA1c, FPG, and diabetes remission rate. Liraglutide reported significant results only for diabetes remission rate (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;39S).\u003c/p\u003e \u003cp\u003eThe GRADE evaluation of the evidence retrieved for the primary endpoint (diabetes remission, Table S3) was rated as \u0026ldquo;high\u0026rdquo; for liraglutide, N/B, semaglutide, and tirzepatide (Table S9).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003e6) Metabolic dysfunction-associated steatotic liver disease (MASLD)\u003c/h2\u003e \u003cp\u003eSemaglutide\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e and tirzepatide\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e were the only two OMM assessed in patients with MASLD. Tirzepatide resulted in a greater effect on TBWL% versus semaglutide in those patients. Tirzepatide, but not semaglutide, was capable of reducing AST, ALT, and liver stiffness levels and it was associated with a significantly higher rate of MASH remission and a decrease of at least 1 stage of liver fibrosis. Semaglutide and tirzepatide were both associated with a greater reduction of liver fat content in comparison with placebo (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Figs.\u0026nbsp;40S and 41S).\u003c/p\u003e \u003cp\u003eThe GRADE evaluation of the evidence retrieved for the primary endpoint (diabetes remission, Table S3) was rated as \u0026ldquo;high\u0026rdquo; and \u0026ldquo;low\u0026rdquo; for tirzepatide and semaglutide, respectively (Table S9).\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003e7) Obstructive sleep apnea syndrome (OSAS)\u003c/h2\u003e \u003cp\u003eOne trial with tirzepatide enrolled patients living with obesity and OSAS\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e, reporting a reduction of the AHI (i.e., the number of apneas and hypopneas during an hour of sleep) and a higher percent reduction of AHI (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;42S, Panel A and B).\u003c/p\u003e \u003cp\u003eThe GRADE evaluation of the evidence retrieved for the primary endpoint (reduction of AHI episodes, Table S3) was rated as \u0026ldquo;moderate\u0026rdquo; for tirzepatide (Table S9).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003e8) Knee osteoarthritis (KOA)\u003c/h2\u003e \u003cp\u003eSemaglutide\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e and liraglutide\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e were assessed in patients with obesity and KOA. Semaglutide, but not liraglutide\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e, was capable of reducing knee pain and ameliorating physical function assessed through the WOMAC scale (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;43S).\u003c/p\u003e \u003cp\u003eThe GRADE evaluation of the evidence retrieved for the primary endpoint (reduction of knee pain, Table S3) was rated as \u0026ldquo;moderate\u0026rdquo; for semaglutide (Table S9) and \u0026ldquo;low\u0026rdquo; for liraglutide.\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThrough this systematic review and meta-analysis, we aimed to investigate the efficacy of different OMMs by analyzing available evidence from clinical trials across different patient categories and ORC. The efficacy on TBWL of currently available OMM is widely heterogeneous, with tirzepatide, semaglutide and, to a lesser extent, P/T showing a greater efficacy than other OMM. These differences in % TBWL were also evident in the proportion of patients reaching pre-defined targets of weight loss (e.g., 5%, 10%, etc., of initial body weight). The results of different OMMs on waist circumference and BMI are consistent with those for TBWL.\u003c/p\u003e \u003cp\u003eSeveral patient-related factors can affect the amount of weight lost with each treatment. It is plausible that patients with a higher body weight at baseline experience a greater weight loss with treatment, as already reported in particular for MBS\u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e. Differences in mean baseline BMI of patients enrolled in trials with different OMMs should be considered in the interpretation of the results of the present NMA. To address this possibility, we performed a subgroup analysis of trials, which enrolled patients in different BMI classes. Notably, few data (only with semaglutide) were available for patients with BMI over 40 kg/m\u003csup\u003e2\u003c/sup\u003e, and none could be retrieved for those with BMI 27\u0026ndash;30 kg/m\u003csup\u003e2\u003c/sup\u003e. The large majority of data were collected in patients with BMI between 35.0 and 39.9 kg/m\u003csup\u003e2\u003c/sup\u003e; in this category, differences in TBWL were similar to those observed in the whole sample. However, due to the paucity of data, observed differences in efficacy cannot be generalized to patients affected by overweight (i.e., with BMI 27\u0026ndash;30 kg/m\u003csup\u003e2\u003c/sup\u003e) or to those with a BMI\u0026thinsp;\u0026ge;\u0026thinsp;40 kg/m\u003csup\u003e2\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eMost trials included in the analysis were designed with TBWL as the primary endpoint. However, there were some studies which were designed for other purposes, e.g., prevention of cardiovascular disease\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e or T2D\u003csup\u003e\u003cspan additionalcitationids=\"CR47 CR48 CR49 CR50 CR51 CR52 CR53 CR54 CR55\" citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e. The results on TBWL after the exclusion of trials that did not have TBWL as primary endpoint were comparable to the primary analysis, strengthening the reliability of comparisons.\u003c/p\u003e \u003cp\u003eThe presence of T2D is a negative moderator of the effects of some treatments, such as MBS, on body weight reduction\u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e; however, scarce evidence is available for OMMs. The present NMA suggests that patients with T2D experience less TBWL than those without T2D; this could be partly due to differences in baseline BMI and age, since patients with T2D enrolled in trials on obesity show, on average, a lower BMI and a higher age than patients without T2D. In addition, some of the patients with T2D enrolled in clinical trials may have a relevant glycosuria. The improvement of glucose control, directly determined by the medication (as in the case of GLP-1 receptor and dual GLP-1/GIP receptor agonists) or consequent to weight loss, can reduce glycosuria, hampering weight loss. Moreover, background therapy, particularly some medications such as thiazolidinediones, sulfonylureas, and insulin, could negatively affect the efficacy of OMM in patients with T2D.\u003c/p\u003e \u003cp\u003eIn patients with T2D, when analyzed separately, semaglutide and tirzepatide were associated with a greater reduction of HbA1c and FPG in comparison with other agents, producing a T2D remission (discontinuing pharmacological treatment) in a relevant proportion of cases. In addition, semaglutide and tirzepatide appeared to be more effective than other medications in preventing incident T2D in patients with pre-diabetes. This is not surprising, considering that tirzepatide and semaglutide evoked more pronounced TBWL and also have glucose-lowering effects by slowing gastric emptying, stimulating insulin secretion, and inhibiting glucagon secretion in a glucose-dependent manner, independent of their effects on body weight\u003csup\u003e\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAs anticipated, all OMMs contributed to improvements in lipid profiles, with orlistat demonstrating a greater effect on total cholesterol reduction than other agents. This aligns with its known mechanism of action, which involves the inhibition of intestinal fat absorption, leading to a reduction in serum lipid levels\u003csup\u003e\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e\u003c/sup\u003e. Most OMMs induced a reduction in triglycerides, which appeared to be greater with OMMs producing a greater weight loss, as expected \u003csup\u003e\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u003c/sup\u003e. Consistent with prior literature\u003csup\u003e\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e\u003c/sup\u003e, OMMs inducing weight loss also improved blood pressure, with the notable exception of N/B, which was associated with an increase in systolic blood pressure. This is a well-known side effect of N/B, and it is contra-indicated in patients with uncontrolled hypertension\u003csup\u003e\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWeight loss generally induces a reduction in cardiovascular risk; so far, this effect has been clearly demonstrated in cardiovascular outcome trials specifically designed in patients with obesity only for semaglutide; while N/B did not show significant cardiovascular benefits. For tirzepatide, CVOTs are still not published. Hospitalizations for HF are reduced for both semaglutide and tirzepatide, highlighting their potential role in managing patients with concomitant heart failure. Cardiovascular mortality was significantly reduced with semaglutide and N/B, whereas the impact of tirzepatide cannot yet be established, as CVOTs are currently being analyzed.\u003c/p\u003e \u003cp\u003eWeight reduction has long been considered a cornerstone in the management of OSAS and KOA. Tirzepatide produces a significant reduction in the AHI, reinforcing its potential role in OSAS management. Similarly, semaglutide demonstrated efficacy in reducing knee pain and improving physical function in patients with KOA. Although those benefits have been demonstrated only for specific OMMs (i.e., tirzepatide for OSAS and semaglutide for KOA), it is plausible that these effects are largely driven by weight reduction, rather than by unique pharmacodynamic properties of each molecule\u003csup\u003e\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e,\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDespite their critical role in clinical practice, QoL and mental health have been infrequently studied in clinical trials, limiting the strength of conclusions regarding the impact of OMMs on these outcomes. In the few trials that assessed QoL, semaglutide and N/B determined marginal improvements. Future studies should prioritize the inclusion of QoL assessments to better understand the real-world impact of these treatments. Importantly, there were no significant concerns regarding suicide risk or major depressive events across the included trials. This finding is reassuring, given prior concerns regarding potential psychiatric adverse effects of weight-loss pharmacotherapies\u003csup\u003e\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAll OMMs demonstrated a generally favorable safety profile, but there were differences in SAE rates across interventions. SAEs were not significantly increased with any OMM, except for N/B, which showed a higher SAE rate compared to placebo. However, the long-term safety of these medications, including their potential associations with cancer risk\u003csup\u003e\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e\u003c/sup\u003e and other uncommon events, warrants further investigation.\u003c/p\u003e \u003cp\u003eDespite the robustness of the present NMA, several limitations should be acknowledged. Heterogeneity in study populations, with variability in baseline BMI, age, and ORC among trial participants, may influence treatment effects. Notably, limited data were available for people with BMI\u0026thinsp;\u0026ge;\u0026thinsp;40 kg/m\u0026sup2;, the elderly, adolescents, and people with overweight (BMI\u0026thinsp;\u0026ge;\u0026thinsp;25 and \u0026lt;\u0026thinsp;30 kg/m\u0026sup2;). Most trials were placebo-controlled, limiting the number of head-to-head comparisons that could be performed. In addition, the varying intensity of lifestyle interventions in the placebo groups of the different trials may further influence the results for comparative purposes. Furthermore, many trials lacked comprehensive reporting for key outcomes such as body composition changes, long-term safety, lifestyle interventions, and metabolic effects beyond glycemic control. Data on weight maintenance, metabolic effects, and SAEs longer than 2 years remain scarce, limiting insights into the durability of treatment benefits. Another relevant limitation of this NMA is the potential for inconsistency. NMAs integrate evidence from multiple trials by assuming that the relative effect of a given intervention is consistent across all included studies. This requires homogeneity in study design and participant characteristics, which may have not always been met. Although no significant inconsistency was detected in the primary analyses (H values\u0026thinsp;\u0026lt;\u0026thinsp;3), differences in trial populations and methodologies should be considered when interpreting results.\u003c/p\u003e \u003cp\u003eDisparities exist in the regulatory approval and availability of OMMs across different countries\u003csup\u003e\u003cspan additionalcitationids=\"CR67\" citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e\u003c/sup\u003e. For instance, whilst phentermine is an approved pharmacological agent in some countries, it is not-approved by the regulatory authorities in others. These regulatory inconsistencies raise equity concerns, as access to effective obesity pharmacotherapy remains variable across populations. Addressing these disparities is crucial to ensuring equitable management opportunities for people with obesity worldwide.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis network meta-analysis reinforces the need to tailor obesity pharmacotherapy to the severity and type of ORCs, as certain medications demonstrate more pronounced effects on body weight and/or specific comorbid conditions compared to others. Overall, most OMMs are effective and safe for promoting total body weight loss and improving ORC. However, the impact of OMMs on specific complications still requires further investigation, and the information already published in 2025 reflects a rapidly evolving field that will need ongoing updates.\u0026nbsp;\u003c/p\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003e\u0026ndash; Effects of OMM on endpoint Total Body Weight Loss (TBWL%) for different baseline BMI categories.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eEndpoint TBWL%\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\u003eBMI\u003c/strong\u003e (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026lt;\u0026thinsp;30\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003e30-34.9\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003e35.0-39.9\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026ge;\u0026thinsp;40*\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eOrlistat\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eNaltr/Bupr.\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eLiraglutide\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ePhen/Topir.\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eSemaglutide\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eTirzepatide\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003e*Data derived from traditional meta-analysis versus placebo; BMI: Body Mass Index. \u003cstrong\u003eNaltr./Bupr.\u003c/strong\u003e: Naltrexone/Bupropione; \u003cstrong\u003ePhen./Topir.\u003c/strong\u003e: Phentermine/Topiramate.\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4 \u0026ndash;\u0026nbsp;\u003c/strong\u003eEffects of different OMM on body weight parameters (placebo-subtracted effect) in RCTs specifically designed for body weight reduction.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cimg 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hyR79uwSOXJkuXXrlnTs2FEbYvjw4R8p6PXr16VWrVoab8SIEVKvXj3JkyeP1K9f/wl73Lx5s9SsWVM7WOz2WYHOt0WLFvLVV18JA1VICYj6wYMHS9++faVdu3by22+/SYkSJfS7Z5V3x44dyoQyM0i8//77giCqVq1agIpNh1i7dm3Jnz+//p8xY0ah/uhDXn75ZSH9hAkTBiitkBTpzJkzkjp1ah1csRXCypUrZcyYMTJy5EhJkSLFcxVn3LhxKuq2bt0qyZIle2paj9sz9U674f6xYsXSax4+fKjt4+eff35CIDxXBl24mHx36NBBokaNKjdu3JApU6ZIpUqVdLKKuD1+/HiQ3vWvv/6SyZMnax02bNhQhg8fLjdv3lT7ZZIMw5kzZ8p7770X4PsePXpU7aFp06ZSvHjxAF/3X0TEFrCrzp076+T/nXfekS+//PK/uLXe488//5SePXvK6dOnZdKkSVrPjwfqhH5+woQJWhd//PGH8iS/tC3/oWLFikL8qVOnav/vtUC+EItoK/KJlkqXLp32yTgE5s+f/5+NLw8ePJDEiRNLwYIF1ebpDz766CPp37+/lCtXzg/d9u3bVc+R9w8//PAfkYYYgfvrr7+qkmdAwvAiRYokuXPn1kGKAh87dkyYmRYpUkT/ZwZCRTEbYyBt3LixdkzRo0cXvBg//fSTpEyZUt59910Vyrt27RKECOmTbpQoUWTLli0qVu7fvy8XLlyQokWL6izt4sWLmnby5Mn1Nyc9SBcrVkxeffVVr9mx5ScICVDnc+bMkV69eqlQY4Y7Y8YMadasmSxatEiyZMmi9vTGG2/IqVOnJFGiRNKmTRttuE2aNJH169dL5syZJWbMmLJq1SrNWdKkSSVs2LDaqdChI5bxVtLoV69erXFIhw41fvz4OqDy/ZIlS/zsNQiL6FpStE9ED22MiSoijLaJoKc9UibKGDt2bLly5YqULl1ahUPLli1l7ty5sm7dOmXENZ988onyRSQ7fPx7BfkOITB27FhZuHChLF26VPuG8uXL6/3oC6ir3r17q4Detm2b1gvCgXaOmObfN998o9+dPXtWIkSIoP0A4ob+gQ6ZjpjrAurtcQ3uYwljZ1WqVNFVA8fDunPnTrl7967gGWFyhE1RB0wa6OvwQDFQ0w/Ch3LBFx63b9/W+FzP99TJF198oRwQTbCCx/79+zUnT7PnTZs2qSjjfniADx8+rAMrooYJDqsb1BHth7p76623NK5XApNTnCaffvqpdOnSRScMCHwE2Z07dwRBAz/yTPuHGSs3CCfKjd074w1tnhUFhwdj2uMBm2NShhCl74AJfQNCmj4IQUJ/RP3ADeZp0qRRYfjLL7/o2ESdHDlyxG+8c/iyIkIc7kEgv4yHwRmwHcZQJhJlypSRHj166D+Y0T5hjIcc+8OpgA1jdz/88IPaZpIkSdQeaa+II+wY+4YPARYRI0ZU+6fspOmIWFjSB9G3cA/6F+o2Q4YM+pl65F70T/Tn6AUm5jg5sFfn/tg0vPlMGRBjjBWOvZMP7APb9kLAScgEEztau3atZgn9hI2VKlVK2zNtnn4AzYN2QhATUqVKpfaG/qJ8tGXiwJfPtBW4Uj+sGMGPtgAvNB02x6SG76lLvMaMp/Bi7CMN+NLvUq98h8MCcctn2s4/6a8QI3AxeGYazP4dw6hRo4YOll9//bV6dgHPAMisGgB4fBi8GKDw9mC4iGGWyYC9Z88ejYNIoSKYBeMZokEx4FFJwMdI582bp4Mh39Gp8T9LcwzITnoYO7M/OiILLy4BBgTsg0kOHlkCwoFBCHvLlCmT/k5HTWOnETO5wrYQbsyOGSCxW+yHiRudBIMT1zG5wiPArBWbpSPGS4s4ePPNN3VZke8ZEOkQ6IQQI14PCFa8hgwitFUEJ4KKcsGDdkQ7p0y0azpWxOP48eN1MEfYIiTwrtCeEVhMXungYIh4eHyAZrDhN4QJQmH06NHafhG4eG7xYiGc6XSd/iRMmDDa4Xft2lW9vR988IEypl7wllFvV69e1QlL2bJlJUeOHOqRp569FLA5mGKbzvIo4hxPEv0UgpLBg0kH9ofIxNbo55io8Tv2zGSKQT1OnDg62cAWqS/i4bml73V4UQcM6Ax8eMz52789Y794ImkDiISsWbOqeMEW6Iu5nokiooO+l4GQvHhFDJB/GGJH2B+2tGbNGv0b+2byxNiDCMXuqAMGZAQn2xgoC+WFF+MKgz/2hz0+Tchj34xf/A5r7sHEF6E2cOBAFXCff/65eg5hh2BGDAwdOlTFCv0E/8gDYpu80pYYSxkLSRcvHXnFjrH14AyUhUkCNkW+KQu8GFsRRHBkUk9fQHnocytXrqxcEFnYMm2ZfhWbwhlA2fif/pUyU0cwpG74jrZBu2a7Dau81C99BX0JdgovVnho4+SLvpZrYcX96c/otxFlpIV+wP4RhNQ57Yq6w96ZVLBlgb6C8eBpk5r/mj+TU+wxX7582t4JsKdfpm9Fz1AH9HfoJsTqggUL1PbpD2iblI2+hMkE5abM6Cri0J6pM9KHHxNu2gj9A30wfQ7McEKQLv0//HFOUs/YLP+YYMAbLUYd8D95/Cf9FSIELp0rA9TJkyf9ZmJUAoBouHQAGCeDJ1CdZTA6TIyI2RsNOV68eGqALA3TwJnJMgBirAysdBBUEgbL4EZl4kFyOgk6XdLkN2YS7K9hYGC5gkbDYIjHZMCAAf+1jdr9/kMCzBzpEFhGwQYJdMx0tEyuHKFK42P2TydAB4BHDUGHtxd7pCPFa8akzQnYcOHChXWAwnuAgKIh02EiKEiHgZEOlXiIj5ASGHzp4Gk/tCM6TsQiQoYOjvZHO6c9whcPDQMPYoFlQNoonSXi0vHAwoWJBoILz8zjgQELLwC/M0iRLiKDvuDy5cs6kYChsyxK2nAnHvXHoEka/I7HHeYMeMSjH6FTpkxeDNgmfSeeEWySgJcZG0JM4SnBzrAlygF7yo4HkvI3aNBAJ2j8jhccMcqWB/pa+jn6R/o+JvsOLzxnDIRMHBik6Esde6avRURR97QDBk88wPxNmnjTHAcE7Qj+eElpb8+7nSIo6geBBQ/6fdoikx4msUy2KD9lYLsCAzmiiokA7BBaCDD6B1ZsWHWgDhi0sSnGHOzZ6UucvGK3jqhi0GfihRhAWMGF+kJ4MEYRjzGNe5E/7B1xgMCCH4IPAcbqI0u+tEXikF+27XH/119/PSgwPVcalMdZ5aLvxAbgxJhOfhG88MI+du/erVs2KCNCiX4FgUQ/QH1QbuyJCTLX0gaoN+wPhxaTByba1AfxaQvUL6sdbD+AtWN/ODWc+nP6d/oj6sx//44QJ014MiYw8aG/4J8z8cAxRp9PPmgvwR0eH8+cCRiTKBwKTBoYq7Av2KKbmKQyacDWcPIgkukjWJVzJmxMDphMM+7BAS70M7QXtBLpwZA6hhfjKf+YkJM296WfJX3aFtuhnAkwLAOiv0KEwGVGgAHSOTPgETA+OmkgMOjRkVAZNHTi0hFj8HQ2LFtiTMwm8NJgbIUKFdJ0GDydGTKzcyqVAYvOi06KCgM26bN8litXLvVKkD4dO4MEs3CMngGAWYeFF5sAM1BsjGUcZq8sy+BNYZ8c39HJ0sjp4LANOmEaOd8Th86ABo2HhYGOQY4ZLZMvbAoxhYcBW0Vw4LFk8Gcg40EcZq/OntR/24PkpZqgXAyulAVRSYdHZ8rgDQNEEYM6op/y0b7pGD/++GMVEohRBiAmk0winT2mDH7EezzAjhn/xIkT1StEYAnTuZ7OlD6DNsu2px9//FE7W+oCDx11xqDHYER9kW86dgZcvF506IhwLwb6TAYR+jnEAIGBHNHgeGrx4iLg6d+wZ35newzlpI+jz0SQ4Umn/GzLIE2uZ2Cmf8Srgs0zCMGLAYk+1/E4+rdnvDjwgxv/mLxR5/DmM+2FVQuEr7Nfkf7eKxMIhJTjdaW/Z9xBADFhYhxBrNMXsDSOYwW7oh9wnhHBTmnXcEecMXHFm8eEDgHGmOIEtiIwmCOM/U+AcfKwQkR8xijagDPBo39g0Cdd6g7bZ7zibyYi2C0ecVaAEAi0RcZU56FDL9kxYy19KmKQ7YH0odgEfQMTL35nsoSdY8NO+dgaQD/L2M8qEKKUNo89Uk84q5y2y0QO+6IfZrKK3aMFqDv4wgfhDHPygsBiou2/vpkowxcPOvbLeIAXlH4dAY2gIy3yR/si/3hzmXzQlrwQ4AVTbJFtFXho6Q+Y/DBZZWXbsTe2KsCCMjN5QPDSn9JmnW1N9A+MZdgekyp+Jz36DDy4/id0tHcmbvQBTIThQ73hQGQLD30J8emHmQjT7miD2D5ajbHhn/RXiBC47PcAEHtFGLTwSjAg0XHjDWOpgt+BTgdDx4mRYbSIVjoVGgoCF68CHS3eHCqHwQ8vEg3A2XNCuszw6IhoMHiA6ZjxhFABdDxUHHttmUUzKPrvnLxgtJYH9wgwUGBveEvwYiFYEWR0uNiMf48jjdf/ZyZBTMIQEAgLbJcGTKdBZ8mToSy5MHFzBC6ijw4d+2bFAnvk/sx0vbJ0GxDatCEGdgZZBhHKxCDDgMOEFbGDWGLrEOIBMY8H0GlvDNh4mZwBBHHFAObsMXX2HMKTQAdNf8CAxOoLYoF2jwig3dJp0i8gCBhwGEDxKHAdnTV9i+PhwqPDnjy8kAyIiG32A9KXsHeNMtH5emW/KAwZMBDqDDAEyoOYYhsX4p5BCRsiOAIXpgzs2CB9LVwQuJTfEU8MNIg5bJ36ou+kD2SgZOJCHfMdYsC/PVP/XEd9w49+Gk8wjNm6g8hl4GJpmHrwWkCg4g2krp03JTAQ8x1CFgHMpI1Bm/IzjmAvxHcC+zadPZ6MIdgfQgEBgcDAvrEhnDCIJNqAf88ugoy+gvgIXTyL9DvUD4KCNoKAYtJIH4IXDbFH/4RQIU2+o2+hL6Jt0a8gjpmsMUlhEoTQ+a8D7ZdVFVZFaVeM1Yzz2B/jMTbhTHyYbDHmInDoR7Bf9mNi746HGnvH/hC4tHXsDF7YqvNQGNxoE3i0qT9s0KkPrmWMJx3S557UJXlC0NIO2H7jv3/HjumfyBdjA5MP6hj+5OtxL/1/zfjx+zGRwusMb8Y18o9Hl7aKTbNFDPvBnrEL+gy8qdgRfS8TWvoX/qG3eCaKABucf/QZtGf4UU+Iekfg0oawYdJnAoDzAhuGt//+C7t0BK6zHY38cK9/018hQuACDOPDSOgQ6SSYSeDqxnVOxwBAFD2Ng5kUnjL2kLFnh30uGBm/Y7T8z8BJRbFkg/eHz4hZ0mc2QwUiJPjHYMAMA28GFY7xApjBks6Ce7Cnho7laZ6k4DZiu3/QEqCzxfOH9wS7YekScYrNIXaYUDF4OHsXnc80RmalNFb2M2LTLM/jxWTWiy3SKWJfeIaYeGFP2CN2yMSOBk4HTVtgcKIzDY7ByFeiiB2WB+kImcXjlaJ9MgFg4oj4pC0zKMMQIUT5mdQ67Y0BGn60MxgShwHN2WPK34gQRBrX8jdi1Jl80onTKTPIwAxvJXVE+ghqrmHygceGh1ioA+qVAZKJBN8jzOmInT1riF7qn8+sFJEHLwTnLRuIXAYtvKAsUyNuKScCCAZOfhGy/E187JqAuGKwZ8mY61lJwAnAhM7pH2FP/wgXBicCPBBgiD3/9kzdU3f8xrYPxAbthwkcXk94kw/y7rxRA9sP7gefnPpktYT9nQh4JzD40hcw0JN3RD75Z3xAmDGRxdNNQPiypQY7d7aAMH7g2WJ8YusBoh+b5Hfi4rn0HxACzgQCm+S+MGJMpJ75TFqMU/DG9hF+bENgGxCCDUFMf0ObIz3aC4zxVlL/5B8v2X8daI/kh34CG4UFtofNIiixFSbEtFHKjncR0UtbpT9EwKIJuMYRmohKvKjOczQITiZY9NX0B7DAA4zHkfojDeoDG0ULYP/UH15F+g0mJQgwbJX70w/57++ZoOGQo72QHnbOxJ3/qRu0B3kjn/wd3IF+GY8+4h1nH44AJldJXiQOAAAgAElEQVSMK5QZ3cNEF3vGIcP2Ddo/7ZN6Qggz0SUObJmAMHmiLmGPDdPH04+yyoNDx/G6YpvYIfaG3dFX8DvtCQcD4yX9C7ZMf4PAJh3qjfyguf5Nf4UYgcugh4ufGQeBJU0KCDzELrM/5+lrOiFmwjQGOmu+Jy7LMXSqfKYiqTAEBt9xDYHBCy8tULkXgwACBEPAG4zXhntxrf/0uRYhHZI8asHduELy/bEJls6wH+yFhkfjxqPDwM7f2Bu/O5+xOZZ/mLky0CAYsGu2HGBP2BsCwkkPjyA2z0oDfzNjxb7oBLBPbBHxFRLepeu0XwZb58lvykagDAQ+ww82xGcCCRP/7Q0+fAcv2j2DBtczgFMfDNpci5eMCQCDuhP4jbScAGfaO4GlTuoUzuSPfoWJDKINAUc8p307/Q31ST/kfKYevPKgmX/7pHxwJ5/YjvPmBwYRJ7/0b+ytc/ox/ocx9QFz+DJQY6sIBqd/xB4RV3zG1ukjGeD9X+vYM8KXuuU3/7zhSBzaC/mjXTgBG8BL5oXA6gn59N/HU2bnLR6wxB7hQX9Ae/X/2jDaPWVlvKGssGR8Ik3qh3JTVia+eBbZ4vC4CKKOqBMYUiesUDAx5p9Tzwgo51VwiFfGO9LnH22D+5A/2hFthnuwZQGRQz0i9oLjlVbUvdMn+B+L/fd3MIUdHNlSRDnIO/lmzCff/E2fSXkpE/0vbRdu2DzsqCfsETZ4MNlKw8SCa6kP4sAGrg4L6ob27t/e2Rvuv7/nGiblTjzqgv7EsXfqi7w5+iG47Rr7pczYkqOnYEP/4WgftJFjb/63yzj9IfFJg+A8tMdEBQ5MJJz+Gnt37gdD6os+2bE3R6sRj7SpHybEzjXYAW2I+5EfODrXPEt/hRiBG9yGYPc3AkYgZBBgywHLxmxNcN61GpicO+95ZW+eI8IDk05IvgYPlbPlg33MCC88VxbcIcCAj9cXDxme2cC8tx0RhQcYMfz4wQPu5DpkpYq4wjOJJx3xhqcQrzerCBaenwBiHo862w+ctzI8f6qBS8EEbuC42VVGwAi84AQQyiy9IXRDa2CZlS0kBJZfWba14G0CeLrYS4q3y+rrybpihQE+7LvF48gDrIE9IdHblhA8ucOLDV8ecGWrXnAGE7jBSd/ubQSMgBEwAkbACBgBIxDkBEzgBjlSS9AIGAEjYASMgBEwAkYgOAmYwA1O+nZvI2AEjIARMAJGwAgYgSAnYAI3yJFagkbACBgBI2AEjIARMALBScAEbnDSt3sbASNgBIyAETACRsAIBDkBE7hBjtQSNAJGwAgYASNgBIyAEQhOAiZwg5O+3dsIGAEjYASMgBEwAkYgyAmYwA1ypJagETACRsAIGAEjYASMQHASMIEbnPTt3kbACBgBI2AEjIARMAJBTsAEbpAjtQSNgBEwAkbACBgBI2AEgpOACtw7d+7IzZs3gy0fESNG1HuTDwtGwFcCZj++EvM9fqRIkYQjQB8+fOj7xXZFgAhEjx5drl69GqC4FilwBIxx4LgF9KowYcLIK6+8Eqx6IqB5DYnxjK9vtaYCd+3GjdJ/6AjfrgzC2IXz55VXwoWVTZu3BGGqllRoIZA3T24tqtmPezXesnkzmTNvvnDOuAV3CEydNFHq1G/gTuKWqhIwxu4aQuzYsaVyxQoyYtRod28USlM3vr5VvArc8zf/lGOXb/h2ZRDGjhPpZUkQ5RW588C8Q0GINdQkFTFsGC2r2Y97VR4pfDi5ff+BPPzrL/duEspTjh4xvFy9cy+UU3C3+MbYXb5hXnpJnVU3791390ahNHXj61vFm8D1jZfF9iABE7juV4oJXPcZm/gyxu4TcPcOJsCMr7sEfEvdBK5vvCy2BwmYwHW/Ukzgus/YBK4xdp+Au3cwgWt83SXgW+omcH3jZbE9SMAErvuVYgLXfcYmcI2x+wTcvYMJXOPrLgHfUjeB6xsvi+1BAiZw3a8UE7juMzaBa4zdJ+DuHUzgGl93CfiWugncf+H15+3bsmDeHEmVOo1kej/LP8b+7fx5ad6wgcxftty3WrDYz0XABO5z4QvQxSZwA4TpuSKZwH0ufAG62BgHCFOgI5nADTS6AF1ofAOEyS9SiBG4A3r3kmkTJ8r1G9flr4cP5ZVXX5UwL4WRbbv3SJ5sH8itmzflpZdekihRo8qGr7bLwe8PSMNaNWXslKlSqEhRWbNypTStX1dfw9O5Zy85fvSolCxUQP+OFjWqNG/UULZ+u0veTJjoEYLnf/1Vhg0cIM1at5F79+7JR1kyS5p308rgkaMkTdq0cubUKRkxZLB06dlLXo8VS+pWryr1GjWWLFmz+VYTFjvQBEzgBhpdgC80gRtgVIGOaOIr0OgCfKExDjCqQEU0ARYobAG+yPgGGJVGDDEC1ylWhVIlJGzYsDJm0hSJ+dpr8v3+/VKzUgUZM3mKRI0WTQrkzCGduneXNO+mkzrVquj3OXPlVnG7fPFiqVClioyaMEnGjRwps2ZMl9UbN8vyJYtl0fx5MnvhYnnt9dcfIbjh83Wyef166T90mHT7pIPkzp9fLv3vXaAf5ckjg/r2lWq1akm6DO/pdUsWLlDx/EnXbr7VhMUONAETuIFGF+ALTeAGGFWgI5r4CjS6AF9ojAOMKlARTYAFCluALzK+AUYVMgVukrhvSKmyH8vAYcMlfIQIMn70KFm7aqUK3j27dkmb5k1l0ozPhBNrKpUpLaMmTpLo0aLLsEED5OCBA5Irb17p1L2HNK1XT4qXLi0Vq1aTLh3ayb2792TAsOESOXLkRwiSPiez1KxbTzq1bSOFihWTi7/9pnG2bNokZcqVkzz5C/hdc/jgQRk+eKDmxzlhy7cqsdi+EjCB6ysx3+ObwPWdma9XmPjylZjv8Y2x78x8ucIEmC+0fI9rfH1jFqI8uEePHJYCObJL74GDpEadulrS5g3qy4plSyXBm2/K75cuSc169aVl23Zy9vRp3YKA53Xfnj3y4P592bF9m0SLFl2q1a4tQwf0l7lLlkqkyJGlXrVqkjVHDmneuo2EDx/+EYJdO7SXD3PmlEJFi8mBffukVuWKkjptWkmSJKkkSpJYPl+1WiJEjKge21Rp0sgvP5+T3t26Sp+Bg5/wBvtWNRY7oARM4AaUVODjmcANPLuAXmniK6CkAh/PGAeeXUCuNAEWEEqBj2N8fWMXogTu6hUrpHnD+uqhzfs/r2nGlO9IybIfS7c+fWXGtKnSt3s3mbN4iW5fKJYvr7Tr3EUWzJ6le2hXLV8mRw8f1u0Eb8R5Q1q1/0RFMXt4e/brLxWqVH2CXvWK5aVardqSv2Ahv9++P7Bftm7ZIvfv35foMWLIa6+9JhcvXNStChd++009wj369pOEid7yrTYsdqAImMANFDafLjKB6xOuQEU28RUobD5dZIx9wuVzZBNgPiPz6QLj6xOukLUHlz2wixfMl7VbvlDxeO3qVXk3WRI/jy7bCUYMHiTzl6+QJEmTSfaMGeStJEl0iwFbBnhQje0M8eLHl35Dhsr7H2R9ZA9v1g+zP0Gve6eOkiVrVilSvIT+dv3aNZkwZrQUKFxYNm/YKEnfTiaRIkWSH8+elao1a8nFCxekd9cumj4i24L7BEzgus/YBK77jE18GWP3Cbh7BxNgxtddAr6lHqI8uEXy5JabN/+QdV9sVdG6asVyqV+9muQtWFASJXpLvty8SRo0ay5Va9RUChlSJFfB2aVXb2nYtJn069lDhg8aKOUqVpIBw0dI1KhRdQ/vyCGDJXe+/OqJLVGmrLz/wQd+FCeNGyvhwoWT2vUb6HeTxo6RsOHCSfVateX48ePSpX1bffMCAhjRe+j772XM8GEyZtJk3SNswX0CJnDdZ2wC133GJnCNsfsE3L2DCVzj6y4B31IPUQL3yOFDEiFCBEma7G0tJdsLfj73k1+Jw4ePIClTp/b7TPyHDx7Km4kSqZjllV9sIYgVO7bEjRdP4/36yy9y8cLfD40R4id485G9szxItnr5MhkyarT+zt7eWG/ElldfjaSfD+zbKxEjvixvJkwor0aKJAvmzpGfzp6VNp909K0mLHagCZjADTS6AF9oAjfAqAId0QRuoNEF+EJjHGBUgYpoAjdQ2AJ8kfENMCqNGKIErm9FC5rYeIB5IK1B02aSOEmSf0z04cOH+sqy1h0+kfTvZQyaDFgq/0rABO6/InruCCZwnxvhvyZg4utfET13BGP83Aj/MQETYMbXXQK+pW4C91943bnzp6xdtUq9xu+mS/ePsfEo9+7WRUaMm+BbLVjs5yJgAve58AXoYhO4AcL0XJFMfD0XvgBdbIwDhCnQkUzgBhpdgC40vgHC5BfJBK5vvCy2BwmYwHW/Ukzgus/YxJcxdp+Au3cwAWZ83SXgW+omcH3jZbE9SMAErvuVYgLXfcYmcI2x+wTcvYMJXOPrLgHfUjeB6xsvi+1BAiZw3a8UE7juMzaBa4zdJ+DuHUzgGl93CfiWuglc33gJD5KdOX1a3337Rpw4Pl79/NH37dktiZMklWjRoz9/YgFI4d7du3Li+HGJlyC+3L17V86cOiXpM7wnx44elbffeUdefvnlAKTibhQTuO7yJXUTuO4zNoFrjN0n4O4dTOAaX3cJ+JZ6qBW469euka+/+koePHyoxMqUKycZMmb6V3p37tyR8aNH6kNnxUuV/tf4j0fgXbwfV6woyd9J8dRrOUiCwygKFC4iMWLGfCQOB1uUK1FMZi5Y9J+J6yuXL+v7gytUqSKXLl2SsSOGy/xlK6Rn507yccVKkjlLFp8ZBPUFXha4f/zxh3w6ZbL8dv68Frv3gIFPFJ/fli5cID///LNEiRJF6jRo6Lljnr0ucHnAc+rECToBrVqzpiR4M+EjnDmum5MMab9vJU4sZcqVf6J9BbVd+pqelwXui8CX+vAq4+1fbZVN69fLvXv3JPk770jpcuUlcuTIj5gQv3+xeZN+x7vaCxYpqq/N9FLwmsDFKfP5mtVy9swZqVm3nh/TJQsXyN7duyV8+PCSt0AB+TBHzicwTps4QU6fPi0RI0bU/iJVmjTBjtprfAGCRoAngbHLCUePHJbZM2b8o70e+v6AzJs9W+PkzJVL8hcqHKSMQ63A7dG5k4QNG1aKlyqlQDkZLSAnjz2vwP1+/35J9NZbEjVatKdW5C8//6yHR3Tv21/j+Q8Y0Y5t22TwyFFBagT/lNjTBO7K9Rtl6aKFcvjgQenco+d/lpdn3cjLAnf0sKGSIGFC+fP2n9K5fVvp2qu31KpX368odMCTx4/VA0Kq16oj3Tp2kBy5cknXXn2Cnav/DHhd4MJ5zcoV8sPJkzJ3yVLJmPl9v+z/+usv0rF1a8n0/vuS+t13pWeXzlKnQSOpXL269gFeCV4VX/B5EfhSDi8yPn3qlLRt3kxKf/yxvBE3rrRv0Vz6DBosRUuU9DNN3ulep2oVadGmrTBpZjI3bso0Sf/ee14xX82H1wRYi0YNZN3q1fru+6Vr1kqs2G/I7l3fSpf27aT1Jx3l6KFD8sXmzfqee/+vAd2wbq00b9BAZi1cpGPd+fO/yrDRY585bv9XleA1vugDGH+5ebOkTZ9eVm74ewK2c8cO+aR1K2nYtKm8kzKlvPZ6LImfIIGECRPGD9WO7du0Huo2bCwpU6eS2G/E0VNmgzKEaoGLgPQvNgCbPEF8KVG2jMyfPVsKFy0mE6Z/qrzxXI4aNlRnc7ny5pOCRYqoB9eJv2DOHEmXPr0sW/u5vBQmjHy+Zo20a9FMrl27JiXLlJUR48briWh5P8wqg0aMlJPHT8iZM6dlyYL5cu7Hn2Tg8BFSpUYNSfh6TN0KwMx80ao1ekywExrVqSWlPi4nBQsXkQcPHkj/Xj2Fk9Y41W3gsOFSsuzHUihXTj26mGOIv/t2p/Tt0V0WrVwt40aO0PyHCxtOuvbuLRWrVpPPpk2Vb3fsELwHVWrUlCYtWkq1CuXku507JV+hwjJszBj56+FfT3hwEbinTp6UBrVqyIavtgelPQYqLS8LXKdAHDCSJ1tWyZM/n4yaMMmvnJd//11qVq4olapWl0rVqknv7l3l+337ZezkydoZeyV4WeCePvWDtGzUSIqVKiWD+/V9QuAePXxYmtavK/WbNJGcufKo3RYsXFQ/0ya9ErwovmDzovD1qsBFcDWtV0/6Dh4iyVOkkEqlS0rT1m2kQuUqfqaJ97Z+zeoquP766y9p07SpDB83Xj7Ils0r5utJgZs+RXLJX6iQOoYQuDFivqZj4b69e3VMvnblihTOk0tGT5osufPm0zLAl/6CQ6LGT5uuKz89OnWUFes3BrkA87XyvCZwz/30o7Rq0lhXxv56+FAFLvzgtXfPbpm7eKkWMULEiOot9x8a1qopP/14VhYsX6lfR3z55SDvj0O1wL1165bkK1BAokaNJmnSppXIUaLIm6/FkO59+0n5SpWleIF8KjzZ7zpq6BDp2W+AzkDqVKsidRs2UoHrxOdz/RrV9dhgZjLjR41Sb12kyJFlYJ/ekjpNGilXqbLky57NT+COGDxIZi1aLL9fuigzp0+THv36y50/7zzTg5s/x4cyYvwESZ3mXUFQ0zGSPwbwgX16Sf+hw2XV8uWaXocuXaVdi+aSNXt2eeONOLJg7mzp0be/LoHxrt7mrduqsJ08bqzMmL9Akr2dXDau/1xixowpKVOnkab160m1WrUkXfoMTxW4bKXInuk9+fbAQXn5lVd8badBGt/LAvf27dvy1RdbZO+ePbJ0wQIZN3WqvJcps1/58djnyZpFPfYI3Mnjx8mKpUtkzKQpT3jwgxSaj4l5VeAy0Zv16XQ5duSIZHz/fenYpvUTAvfatasyauhQmTB6lGTKkkVu/vGH8k2RKpWPFNyN7kWB+yLx9arAZfI7bOAAdThk/t8x8dgnp2M6gVWITm3aCJ7FJMmS6Ra3YWPH6QmdXgpeE2D379+X8aNHyfzZs1TgRooUWbp1/EQuX76sAvePGzekRIF8OuY7Ww453AmBGzPmaypwv9i0UcfDNZu/kISJEgUrbq/xBQYrCk3r1VXdgcB1Pm/b+qVkzvKB/PLzOcmWI6d069VbXnn1VT9+GVIklxs3bmic48eOSqWq1aRtx05ByjdUC9yzZ07rUmbsN97QfTivvfa6pEqcSFZu2Kh7bBvXrS0lypSVlyNGlO1ffSUt2rbTWYj/Pbj+4y9eMF89onny59fl+4bNmqt3Vb20P/2knwvn/shP4OJhZbsB+4PGjhwu7Tp2knv37j9V4N68eVOyZkgnazZtkQRvvqnitUjxEpI7Xz71+NIAm7VqrfkbNmiAtO/cRZo3qC+fzp0nX33xhUyfPFnSvZdBHtx/oHlp2a6dHDxwQL79ZocudTmBxk/YtP5zTSNnrtxPFbjEwUDnLl0uKVKmDFKj9DUxLwvc69ev68DFHsbtW7dKxapVpXb9BiZwfa3kZ8T//fdL0qpxY93XHi58eGnZqOETApdltDkzP9OlSmyV5TQmhh/lyfPIklkQZSnQyXhR4L5IfL0qcNmDzz79/f/fqxg9enTZv2+vTsAyZPy/0zDpsyeMGS0H9+9XkfDHHzdk1PiJkjhp0kDbmxsXek2AmcB1o5YfTfNZAhf2rDigfwb17SPL1q2XOHHjPiJw06RNJzMXLJQh/fvpavTxn34O0gyHaoH7tC0KzxK4u3ftkkbNmkvYcOGeKXDZUH3y+DHJ/lEu2bd3tzRq1kJeffVVWTBntj5khMBlC4GzRcEXgYuxZEqdUlZt3KwCl70r7NXkQQM80QjcTt17yOuvvy7DBw/S/69cuSLdeveR5YsXy/ZtW6Vs+Qq69YGlgERvJZaFc+c8InDxNCOWi5UsKYP69lUx9m8Cd+nadfJW4n8+wjhILfYpiXlZ4DrZvfPnn7oi8Pvvv8um7Tt0ICNc+O28lChYQFq0aace3P69e8qeXbt0gAuOt3Q8q6686sGlXZYpUkjiJUggtJEfz5yRQsWK6WqFs6eO5Uk8MuOmTtOJK/sdic8KCxNQrwQvCtwXia9XBS5eWfrzyZ/N1IdLmzWorytv9AnOQ2Qzpk6Rrh3ayzf7vxc8jC0bN9QHeqrWrOUV89V8eF3gRokaTVc7z545+/cWhatXpUje3DJi7Hh1chFwSuCR5E1JeHDZ20/9rNqwSfuN4Axe4wuLZwncG9evyeLVa2XlsqX6UPrjWzxwkLEasXjVGnXw9evZU36+fDVI8YZqgRs3Xjyp9r8OInyECOr9fJrARcD16tJJ+gwcLPcf3JcieXLL8LHjdEkjTtTI0qBJU90SkCNzJhkwfLi8mTCR9O7aWXoPGKRbFNj7WqhIEcmRK/cje3CfJnBFXtKHYPDypcuQ4ZGHYEoWzK9LKSxxL54/XxYvmCdTPpulT4NiRB26dpUoUaLqTH/M8GHagAsVLSZ7vtsl82bNUg90jBgxJEzYsLqXmE7Tvwe3bNEiUr1OHUmRMpW0bdFM6jVqLDk+yvVUD+7Fixclb7YP5MCJH4LUIAOTmJcFLsKqQ5duWqwieXLpsjgec76/dfOmzF++Unp16ax7mHhgjwlQmfLlpVP34H94z39deFXg+s/jujWrddWCh8yix4ghxfPnk1x58+rSFxNAjtBOlSa1fNKmjbyTIoW0at9B24FXghcF7ovE16sCFwGFfa7d8oVEjhxFxVWBIkX0ochShQtJp+7dJXy48NKrW1fZsmOn3Lh+XTq0aqH9ebGSfz8k7ZXgNQHGVropE8bLovnzZO6SZfqgE29QYo8oq4/rVq/S1cqR4ybIzE+nqyed/mP3t98q7+9P/CCjhg0RtpINGTlaogTzlhCv8WW/LROuNs2aCqs9PO9Dnzp1wvin8mvfsoWcO/eTOnBwsKFBFqxYJf179ZDo0WPIqAkTg9SUQ63AnfPZDFm9YoU+rEXgAS+W/JvUqyvd+/QVxO+4USMlS9ZskjFzZt1ozr7XVyNFksLFiunvPMj1doJ4+qDagX37VAw2adlS02Pf5bRJk9QjWrRECalcvYZ+37ldG6lVr4H8+svPcuLYcandoIGwB2v1iuX6KhLeKztrxqeyYd06FbMp/e0T7NSujb6Dtvz/Hj4gf1u3bJGYr8VU7/K76dLrPRCtc2bMkG59+vq9GcLJP/lJlTq1epPJM3tfGjdvodf9cPKEdG7XTr1abyZKKKXKfqx7vSg33mJmtquXL9N0eRtEr66dZeGKVUFqkIFJzMsCl8aPR4YQK1YsfZiBPaHs0UbUYmsnjh3TfWJ0ojztO3ri/z2EFhgeblwTEgQu3saJY0dL+05ddGLJRJH98Ng3fNmaQHDsn61JXgpeF7ghna9XBS779NkfzpPnBN6M0Kh5c7l08aL07NxZyleurEKWfoT+hMCDU1Vr1NTVOC8FrwmwiqUfnQDwrMyHOXP68eZVbE1atZIM72XUcW7j+nXafyRLntyPN0/2M77y3vfgDl7j6398g41/no69+uc3dsQI3auL/qD/bVa/nuAsS5gooXTu0SvI3+8fagVuUBmqf49vUKX5rHR4KIzX9cxbutztW/1r+jwMxVOT9Zs0/de4bkfwssB1u+z/VfohQeD+Vyzcuo/XBa5b5f4v0zXG7tL2mgBzt7T/ferG1zfmJnB94/VE7P9S4OJ9rVqurPTsP0BSpkr9nDkP/OVXrlzWPTVNW7XWty8EdzCB634NmMB1n7GJL2PsPgF372ACzPi6S8C31E3g+sbLYnuQgAlc9yvFBK77jE3gGmP3Cbh7BxO4xtddAr6lbgLXN14W24METOC6XykmcN1nbALXGLtPwN07mMA1vu4S8C11E7i+8bLYHiRgAtf9SjGB6z5jE7jG2H0C7t7BBK7xdZeAb6mbwPWNV7DH/vPP2zJz+nR9uwLv27UgYgLXfSswges+YxO4xth9Au7ewQSu8XWXgG+ph2qB+/DhQ3n/3dT6ChZeyfXSSy/pq7A48CB/wYKS639nUztI+/XsISOHDNYTkwjf7Dugxylu2bhB3wP322+/SYnSpWXspCn6rlk3Au9OHdSvr766zDla0I37hKQ0vSxweU/gN19/La2aNJKO3bpLyTJln0C7c8fXaj+nT53SV4l9/uVXnjrkgQx7XeAeP3pUShcppEdR8x5LTih0AnUwd+ZnekTn7Vu35L1MmWTkhEmSxGOnQHlV4HKARotGDWTZokV6LHf7zp2lQZNmfny3frFFz6M//+uvIn/9JXfu3pVW7drrsZtees8wGfYiY8ahMSOGyfBBg/TVgR/myCFjJk2WN+L836lPxOnbo7uMHzVSsOeK1apJ7wED9b25XgpeE7hXr1yRHl06yXc7d+pRvbFivyGwxFYL5Myu777fe/T4Ewix+cxpUsmFCxfkwf37MnjkaKlas6ZqhOAMXuOLLZ48cUIPHiFvHNVLmDd7lnzSupX2x4RmrVtLq3aPvnd8+uRJeiKr86o77Nn/KZ9BwTlUC9wvt2yWYQMG6DvveGk250zv2vmNHszwXsZMUrx06UfeEoDAJXBimBM4oYpjfEmD60sWLCANmjaTIsWLaxQayqkfTsrrr8fSd9Ke+uEHPbyBU9QuXbygojh1mnf1uN5TJ0/ISy+FkXdSptT37BIOff+9cA4575fjgIf79+49InB5D266996Te/fuyqED38vDhw8kSbK3Nf3QErwscHlP4NiRI+Twwe+lSo2aTwjcm3/8IYP69ZEPsn0ohYsVlxFDBuvr1ziEwEvBywKX94jyfmlO1Pli06YnBC5tjoM1OJDlwxw5pXzJ4lK6XHl9t2W4cOE8g9mL4gvBxTGa9GHDx46XqP/yovszp09LlY/LSIfOXaVEmTKeYetkxIuMDx7Yrwc99BsyTJIkTSIFcmSXjt176smGTvjm6+1SrXw5WbB8xf9Ojqqnp2xly57dU4y9JsDyZPtAj0nngAZH4O7bs0d6d0M4mScAACAASURBVOuihznEiBnzqQJ3+KCBMm/WTPl67349KGLm9Gl+1wcncK/xZaJQqUwp+ensWUmZOrWfwOVkspnTpunJe88K6CkOe3jaBCOoGIdqgcuRnbz0+fChg5Ix0/tSqGhRWbF0iUwcM0beTp5cylWuorNpJ1AhHODwwYfZJXWaNOpBffxF2w1r15SiJUr6eVcZfPH6ImIRzI3q1JbYb8SWnv0GyNSJE/Wo1mq1autRdTFixNRb3bnzpzRr1UZOnjwhwwb0V/HDgQxFS5SSj3Ln9hO4NNwd27dL5x49ZN7s2SqMokSJovnDSxVagpcFrlMHCKz8hQo/IXDv3rkjE8eOkWvXrgkvIWfWy0lmJUp7Sxx4WeDu/PprGTd6pOQrWEh6d+3yhMDl+N4m9evq8cgc5jJlwgRp3qatFC9VSsKECeOZZuJF8XX599+lZuWK//98xZckfcaMenxp6XLl5O3kT3/p/ZgRw/VQHE4qSvb2255h62WBe+TwIWlar54kfftt7d95x3jPfv3lozx5/fhxyAZCgrEF5wfH+46fOl0dK14KXhNgE8eMlkuXLsnaVSv9BOqPZ8/KmdOnpG/3bnrI0tMEFoco8c75pi1bybGjR+TmHzdl+Lh/n+C5XRde43v9+jVZtXy5LF+8WG7d/MME7tMMIE6klyVBlFfkzoOHbtuHX/ocF1e3ahU9Wm71yhVy5tQP0qJtez157FlbFDhpihPIbt+6LVMmTtABsmz5Cn5p0hBqVa6kRy5GixZdv8eFv2TBfDl//rwefcvxtnRcLN81rlNbOvfqLed+PCt0YC3bttP7Dx88SEp/XE44bS112nelRu26egrTvNkzZeioMSpwye+bid6S5q3bqGcYD0DZ8uV1kA9tISQLXOqKiUrHNq11olWkRElp3b6DnmjnpeBVgfvnn3/KoD695ZVIkfT4XSatj29RYJls/9696llkeZKVEJaAOTXOS8GLAvfihd+kdJHCkj3nRzrxGjF4kMSNn0CXx1999dUn8KV8K6GULFNGeg8crMu/XgteZIyXfPvWrdKg1t+nXebMlVvGTJ6iJ0o6ATvf9uWXUrlsaT1Nk7HEi1tAvCbAWEHlFMP5s2c94YEtXiCfnPvxx6cKXPpkrmNLyOuxY0ufgYN0chHcE2Kv8cU+WTnjeGlOKHO2KOCwG9K/vzoKX301ktpq9o8+eqQ7wGE4evgweTdtWv1+5oKFj2zLCYq+I9R6cOfOnKnbEfoNGSp7vtslzPTYZ8Mes2cJXP/A2WOC4EWMEBhEs6ZPJ1NnzZJ0Gd57pG5YClm/bq188OGHegRvnLhxJV36DDKob29ZvWmLzJ01U1o2aihhw4YTeUnU88FyYM8uneTbHTv89vN+kC2bzFqwSLp1+kTd/z369ZeGTZvpviCWEMsULSIPHzyQhStXyTspUgaFfYSINEKywL1586Z07/iJZM7ygVSoUkXKlSgmqdK8qx4cLwWvCtyfz52T+jWqSeeevXSiwF7mz+YvlCxZs/rtl2PZHA964sRJpErNWlKiQD7p0qu3HuFrWxT+2cocgdu4RUupXK269OraRQ59f0A9tI9PEDhuvHnDBjJpxmeSN38BL5mvX168KHAPHzyoDoq8BQtK2nTppHbVKjJy3Hi/493JPGNVlY/LSs269fQ40x6dOsqydesfWWH0AnCvCbDAClyE1+C+fWT24iXy2bRpcuTQQVmyeq0eLxucwWt8nyVwHUa3bjG+ddTj6KfNmSsxY/69Su0/sFWzSf16cvPGDVm18e/j1IMqhEqBy7YBBjyWJ155+e9ZMt4zBkbOm8Yj9FHevJKvQMFHOO/ZtUvey5xZvazEeSNuPKnXqJH8+ssv0r9XTylQuLA+sPZ44D4D+/aWCBEiSIHCRbSyaTAJEiaUNh06yvq1a2Xv7l3SrHXbR7wiHdu2lpSp00j1WrX9knQeMuN8Z5YFWrRtq2k6YfmSxbp8xQAUWkJIFLgnTxyXMC+FkShRo0jfHj2kScuWuux78PsDwv4v6s+/Bye469KrAvfwoUPSo+MniufipYty5NAhXf1gT/2lCxd0dYNtQAiIJWvWSfz48aVTu7byyquvSvfeffR/rwQvii+2KFSvUF5y5smjK0ytmzaR27duSp9BQ+SHEyeUb6o0aeTWrVtSPH9e7ePWbvnSK0ifyIcXGa9ctlQ6t2ur3CJHiay2mvrdd6Vug0bC/twkyZIJcfr17Ck//HJeHSuMXxUqV5Eadep6irXXBJgvAvfUyZPChJmtIp3attEJ8vQ5c2Xj+s+ldZPG6oziofLgDF7jC4uneXB/PHtG4sSNpyvYeHK3btkscxYvkfPnfxWeW0LXnP7hB+07HD32w/ET8sXOb4MUb6gUuMyY2WPTvU9fPy8En1mu4BjcSWPHyM4dO6RG3bqPeCJww8eOE0eYlfA0dusOHSVOnDgyqG8f2bRhg+TIlUuX5dJlyPDEXsteXTrLF5s3yfJ162X3d7t0Bo6XNkPGjHL+119k2qRJwjIUHiUeEONp+59+/FHz6Txwxn7hrNk+9NuD+1biJNKzc0dp1qatnDl1Sh9Uo4Hi6a1Vr36QGoqXE/OywKVOZkydIhvWrpW3kiaRjJkyS73GTWRwv74SIWIEadmmnT5Yhu3FiRdPJ0vsw6tY9f8eMPECe68KXP9s1q1ZLc0b1NctCtFjxJDi+fNJrrx55ZOu3XSPY9z48fUtFSeOH5fqdepIoSJF9YFPrwQvii9WpnjYhokzg9Lq5ctk1MRJ2ic5fMdNmSY8sFunahUZOGyElK3wf9u2vMLWyYcXGf/twa2rW2eYIPBGEPaIR4ocSUoULCCduneXrB9ml0qlS+uDe3fv3pHLv1+Wjt266WqPl4LXBFiPzp1k7+7vdOJbplx5KVepkj7rgj1PnzxZbly/Ls3btNHxllXZT6dMlhnz5sv3+/fLtEkTdc/+yePH5bXXX//7rRVRgvetFV7je/XqFRWwONXQRFVr1VYHA3uceTbiz9u3BfsuUaasPjTJSjXbQ3HgfPvNDq2X69euqdMPzVLq44+D1JxDpcBlxnH92lXd7+EMcNeuXpWLFy/oWxPYS8Irm5iBJHjzTT/giEf24BLo4OPGi68zFJZAr1z+3S8eb0x4K0mSRyrqt/O/ysULFyVN2rQ640GQ4i12XqPD76TPHsEoUaLq9fzGLOf33y9pWuQHzy0zeB724AlQBmv+pqHeuHFdwoULr/teIkWOHKSG4uXEvCxwb9y4IceOHPbDxwCWKnUa3ZONhyB+ggR+9kak8OEj6Fs0bA+u7xZHZ3vm1Gm1/7DhwsmxI0ckarRokjhJEm1vly5d1ET9ty/f7+LeFV4UX46HBn68g5s+6d106XUy7p8v20Pw2iRPkVL7I68GLzJ+8OCB2ueVK5cVG89v0P+zUkjfQR/BWPX9/n36GjECr7vCmxjce0Ifr2evCbDvvt35SBYTvZVYbRgBBl8CfTLOIvpq3npD/0FgbL1//+/XXNGHvPZ6rGA3a6/xxR6xSyfgoEucJKk+fE//wNud2DPOd6xIomfgjn0z/h3Yt/fvPjlqNEmaLFmQbxkLlQI32K3UMhCkBLwscIO0oMGYWEjw4AYjniC5tRfFV5AUzEOJGGN3K8NrAszd0v73qRtf35ibwPWNl8X2IAETuO5Xiglc9xmb+DLG7hNw9w4mwIyvuwR8S90Erm+8LLYHCZjAdb9STOC6z9gErjF2n4C7dzCBa3zdJeBb6iZwfeNlsT1IwASu+5ViAtd9xiZwjbH7BNy9gwlc4+suAd9SN4HrGy+L7UECJnDdrxQTuO4zNoFrjN0n4O4dTOAaX3cJ+Ja6CVzfeL2QsXmq8ejhQ5L8nRR60EVICyZw3a8xE7juMzaBa4zdJ+DuHUzgGl93CfiWeqgXuGNHDJcUqVJL3gJ/n7zDS4i//GKLvi4sSdKkj9DkPbYcl+iEpq1a6/n2Rw8flhVLl+jrLziJhne+PS1cu3ZNj/7j3ZwfZPtQo/DuuMUL5uurxqJFiybNWrd55NLPpk2V8BEiSInSpSVSJHde/cWrUXgPIye5JUyUyDcL8kBsLwtc//ULqi49ez1B7OdzP8mKpUv1JC6OP61Qpaq+GshLwesClwMJaCu8Zu9p/A7s2yfrVq/SNpow0VvannhXrpeClwWuL3xTpEolJUqVlggRI3oJr+bFq4y/+Xq7fLFpk3AwAQcNPK2/9z/+ZMycWQ8iYmzwUvCawL13964e1PDj2bNStUZNv9dncoLklAnj9TVrzVq1fibCPt27iZfs2Wt8AXf1yhUdv0T+kuq16/ixPH7smCyYM1s/P81eOUF2zcqVfvELFimiJ3oGZQjVAvf4saNSuUxpPSO5R9/+OuBdv379mUf1cnYy76CtXvvvk8U4kpf34C5dtFDfpcd7CTkM4rMFCyVFylSP1BNHLU4aO1YiR42iR/E2adFKf+dl0kcPHZKPK1WS0cOGSv5Chf2M5Juvv5a+3bvqe+SedjRmUBmCCdygIvlkOuNGjpT4CeKrXXXv1FF69O33SCfA+0RHDB6k71/kReTdO/19bG83j52y5XWBO3bkCFm5dImc+uEHPeghY+b3/Srj/K+/6slEaTOk13cQ047rNWoiFatWtYMeAmj6/8SXyfnaVSv19C36uYVz5mh/lSlLlgCm/t9F86LAhV+7Fs2laIkSEvuNONKlfTvpM2iwFCle3A/M0SOHpW61qtKwWXM90nTmp9Nl7OSpeqiQl4LXBBhHd69ZuUIPali6Zq2+PxjeA/v0lmWLFkqcuHFl79HjTyCEN4cxbVi3ToqXKi1jJk+RyB54t7zX+F65ckXaNG0smzdulHfTppWVGzYpS/oB+twadetJ8nfeUbvGeeb/vc1D+vdT/fPp3Hl6De8ofiNOnCA151AtcIHLTO6PGzckX8GCKiw4JnH+nNmCIXGaTOcePf2AMzA+fPBA2nfpqhX1+Dn2iN2q5T/WEzkeP+bXSWRQv74SKdKrfgK3RsXy0rxNO53h7N2zW2pXriR7jhxT4VyqcEHp2K2HjBj899GtztnvvFC9R6dO0mfQIIkWPYYM6ttbMmXOIsVLl5ZVK5bJ7m93SddevaV/zx4yZsRwNa7h48ZJnnz5hZfht2n6d6PnsIpdBw8L3hnHg8vLl9u3bC7d+/STH06e0NOJokSJIiPGT5CiJUoGqfEFVWJe9uA6Zbx08aLkzppFcubOrQOTExC+rZo01sbfrmMn/ZvTozgtygsdqpNPLwtcBqzmDevrQMQJcY8L3COHD+lJZk1atJAcuXJLverVJF+hQtKwabMgf7H489i0F8UX5fk3vv7LfPb0afnog/dlzKTJTz22/Hn4BMW1XmT83bffav87aMQoSf5Ocvm4eDFhdbBilap+RcYL2aBmDZm3dJmuUrRo1FBPwsz64d8rgV4JXhNgqZMk1onCju3b/AQup+5tWr9ej4/lgKenCdyFc+fK7l3fyqHvD+gBDyZwn25hnLZK3/vg/gP566+HfgKXyQF6ZuGKVXohB2o9fmokemrh3DlP5R9U9hxqBS5np5cvUUwGjxot69eskciRo0jNevVU8DK7y1+woOTKm+8RznNnzpRF8+dqZXIGe8du3fU0siuXL+s2BU4imzPzMz2/mu0GTwuPC9xUiRPJyg0bJWmyt+XcTz9J4dwfycZtX8v6tWvk+rXrKlrbtWj2hAe3Q6uWUqBwEZ3B16lWRT2/9Rs30bxnev99XYqdP3u2nv+8c8fXejRh+05dZMa0qbqkwDHFk8aN1fPk23bspB1skxYt1TNQpUZNyZUnr3yQPq18One+pEiZMqjszZV0QoLA5VjCquU+lk7deqidOQExO3fmZ+pVxLu4f99emTDtU8lfqJArrAKbqFcFLqdAzZ7xqR75iMewY5vWTwhcBrFhgwbK5HFjdWvQtWtXtT2lTJ06sDhcuc6L4isgfIFx6uRJ+emnH9WTi8gdOHyEbgXxWvAi4wu/nZdBffuqHXMkL9sUxkye/Ai/X375Wdq3aCFfbNooyZInlyTJksmIceMlatSnjzPBxd1rAheW40ePkvmzZ/kJXIdN8QL59Ij0pwlcvzj585rA/Rdj4mRWVq45ARYPrvP5qy+2SPqMGYUVtNx580nnnr30NDMnMObNnD5Nxk+drl998OGHQX6CZ6gVuFu3bJGpE8fLjHkLdO/TssULdZtCmLBhnylwnYpBPOJe5xjQpi1bydkzZ+TzNavVE3zht99UIBLY88ds+yPEYrZs+l1ABO602XN1T2+Ltm3l1s1bTxW4eJlpnAjgAb176XaJWnXrSYVSJVXUTh4/Tvbt2aPLhgzweH1HT5wkHVq1Uu9z4qRJ1fA4snDarDkqcBHo7F909iRNGT9evt7+lRon3jGv7Vl06sPrAheuzGg5KhZ7ixo16v8J3Lt3Zc2qVTJ35gxdouE89D4DB0uFKlV024tXglcFLqsPrZo2ljIfl5fwESPoWeePe3CZ0NFeVi5dquKA/Y6Dho/UrUleOurUi+IrIHyxUQaz3bt26SQdsdujXz9Jm95by+fk04uML174TT6bNk2XdaNEjSrHDh9RgeufH30Ie0a/27lTRQIT4+HjxstbiRN7pYvQfJjAdbc6vMaX0j5L4GKjsxctliUL5sugvn1k2br1uiXECV9/9ZX2xTgVVy5bKjVq15EmLf/euhlUIdQKXPaHLFu8SDuIP278Ib/++ots2bFTReuzPLj+oU8aO0auXb+uy8r+A2KTQbN2/QYqHtlqkODNhLod4GkCN0fmjDJ60mRJn+E9OXjggLRu2li3LPTv1UO9ypyFzTnl7GVp80lHv3PeDx38Xrq2by+16tcX9sF8s22blKtcWaZNnCgzFyyUEUMGyY3r19XLS+DhJR6mY09S8hQpJPP/9sfhAXg9ViwVuMSdN2umem15yIlzplmmYTknSdJkntuzGBIErrPHFgHAQ3yp0qR5xF54sAzPLstotRs0VE/u4YMHZezkyRIvvnceNPOqwN3z3XdSpmhhSZgwkdy7f0/34LKVhj3MzuD/zfbt0qR+XZ3gvZ38HWnTrIm8mSiRdOnZ+xGPQlB1qoFNx4viKyB8/ZeXh3lKFy4olapVlxZt2nruISgvMt74+Trp3L6drtzQFzdrUE+y5/zoEX48QMne3O179gnbnVo1aST1GjX2c6YE1uaC+jqvCTDz4AZ1DT+Z3rME7o0b12XxqjUqXnt27iQr1m+UePHjP5EAQhj9sW/3btl54GCQZjhUCtyzZ05Lswb1ZeykKTrQEficJm1aqVarlu7jwyOK19L/vpGSBfPLolVr5NLFC7pXskXb9rp8z9JS2QoV5PVYsaV6hfJSplw5KVep8iMVhSeX/btDBvaXSK9GkkbNW+j+vwF9esvtmzelS6/e0qJRA/XidejS1e9aBoynbVEgAvl5LVYs6dKjl3qLN2/coA/P8DTipvWfy6dTp6h3loDopix8d+aHH3S5gBD2/z9F+ru/Pbhsjdi3Z7eMmjBJvc8YH0u7eLa9tmcxJAhcHkAc0KuXjJwwQR98Yo8zXjEGsVs3bwre+rLFikjZ8hWkfpOmOrk6duSIjJo4UWLFih2kjf15EvOqwPVfpnVrVkvzBvXVg8tqQ/H8+fSNJaxKsIQ2buo0SZ3mXWnbopm+JYUJY0QPPenvRfEVEL51GjSUE8eP655bVrCypE2je3Dh7rXgRcarly/XAX7T19/ovvv6NatL/oKF5f2sH0ipwoWkU/fuEiZMWOnbvZts271XHRcI3BZt2+kY5aXgNYF7+/ZtwRm1YO4c3Q+KB5E+mK03pQoV1BWH7w4d1rGxf6+e8umUydp/ZMiYScdrnoOJ+frrMmr8RIkWPbpeG5zBa3xx4LFC3LxRA7l86ZIsW/u5hA0XTiaMGa32evTHczJ80AA5e+asDBszVjq0bCHnzv2kW8SG9O8rw8aM09Xllo0b6ZacsZOnBCneUClwjx89Kru/2yUlS5fRNxQQ+Lxh7Vr5pGs32bJxg4wePkyfaq9as5YfcPZKLpw3Vz8jSMpXrqJ/8yoMXvVFYEBt3rrtE5XENgi2Ddy+fUt/ezdtOmnbqbM8eHBfHxijkvHusTztPzBgTBo3Rpq1aqMNzH8gP19u3iwTpn+q+R85eJAMHTNOYsWKpdH85zdbjpzSuFlz/X7c6FHy9Vdb9e9yFStJkeIlZPTwoVK/cVN55dVXZdrECerlXTRvnly5cln3Bzdr3dqTe+oog5e3KHTp0E49sk6IESOm7nlevGCe4N2lvh17Iw4e9U49eug7ib0UQoLA3bVzp/DaP/ix+tG1Q3tJ914GbY+0ZzgTELk8xBPUT+w+b315UXz5L9M/8cXDiKcG4ZA7X/5/fPXS83J6nuu9yBgRhn1+s32bFu29TJm0v7948YJ6bStXq66vnmxYq6ZcuPCbxilYpKjUqFM3yPcsPg9brvWaAGN1x39o0LSZxIkTR3njaCDwPA3b8uinP1+zRvuPX879/Mh4HS1adBkyarS+jSE4g9f4ok8a1v57SyaBCVqLdu0lY6bMfvYaP8GbyhdNMXLIYF2BoP/FadagZnW9ztFDPNAelCFUCtygBGhpBT8BLwvc4KcTNDkICQI3aEoafKl4UXwFHw137myM3eHqpOo1AeZuaf/71I2vb8xN4PrGy2J7kIAJXPcrxQSu+4xNfBlj9wm4ewcTYMbXXQK+pW4C1zdeFtuDBEzgul8pJnDdZ2wC1xi7T8DdO5jANb7uEvAtdRO4vvGy2B4kYALX/Uoxges+YxO4xth9Au7ewQSu8XWXgG+pm8D1jZfF9iABE7juV4oJXPcZm8A1xu4TcPcOJnCNr7sEfEvdMwI3WYzI8tdfvmXeYhsBCPDmlv79+svqtWsMiEsEunbqLFOmTZNfz//q0h0s2SULF+orBi24R8AYu8eWlOPGiSt1a9eW3v36unujUJq68fWt4j0jcBNEeUXuPHjoW+4tthHw+GvCXpQKMg+u+zVpHlxj7D4Bd+9gHlzj6y4B31I3gesbL4vtQQK2RcH9SjGB6z5jE7jG2H0C7t7BBK7xdZeAb6mbwPWNl8X2IAETuO5Xiglc9xmbwDXG7hNw9w4mcI2vuwR8S90Erm+8LLYHCZjAdb9STOC6z9gErjF2n4C7dzCBa3zdJeBb6iZwfeNlsT1IwASu+5ViAtd9xiZwjbH7BNy9gwlc4+suAd9SN4HrGy+L7UECJnDdrxQTuO4zNoFrjN0n4O4dTOAaX3cJ+Ja6CVzfeFlsDxIwget+pZjAdZ+xCVxj7D4Bd+9gAtf4ukvAt9SfKnB3b9uqqWTMntO31AIZO06kl8VeExZIeHaZmMB13whM4LrP2ASuMXafgLt3MIFrfN0l4FvqTxW46xbO01QKlavoW2qBjG0CN5Dg7DIlYALXfUMwges+YxO4xth9Au7ewQSu8XWXgG+pP1Pg7t72peQoVFRixY0nkaNGkyjRo0ukKFEkfPgIvt0hALFN4AYAkkV5JgETuO4bhwlc9xmbwDXG7hNw9w4mcI2vuwR8S/2ZAnfq4P56BurdO3ck7psJJW7CRBI7bjx5650UUjiIPbv/lcDdt2ePfPXlF1K2fAWJFz++b6T8xb57966sWblCbt26JZWrVQ90OgG98Jeff9b7/X7pknTo0jWgl7keb8KY0Vr+qNGiBepe1MeNG9clx0e5AnW9c5EJ3OfCF6CLTeAGCNNzRTKB+1z4AnSxMQ4QpkBHMoEbaHQButD4BgiTX6RnCtxLv52XLLnyyLXLl+XY9/vllx/Pytnjx+T61Svy2ZavfbvLv8QOiMDdsnGjIKj6DBokbyd/R5zPterVk0JFi8mxo0elT7eu0qx1a3n/g6xPvePQAf1l2qSJ8vmXX0mCN998JM61q1elZZNGki59BmnZrv0/5hih2bR+PU1j8MhRQcri8cT+/PNPGTV0iJw4dkwqVq0meQsUcPV+AU0c3p3btZHZi5ZIxIgRA3rZI/G+379f2jRrKuu3fhWo60OSwHXs89q1q5Ix8/vSom1biR49xiPl/vabHdKnezf9rnCx4lKrXn15+eWXn4tNUF0cEgTuutWrZNyokVrkchUrScWqVZ9Ycbp65Yp0/aSDnD1zWuOt+HxDUCF67nS8Lr7+je/sGZ/K/DmzH+HQpWevZ/bHzw0sEAl4lfGyRYtk1oxPZfzUaRIrdmz55edzMnzQQBk8crRfKeG7cf3nMmLseIkWPXogSu/+JV4XYLdu3pQxI4bLtq1fKozGzVuofvAfzp45IyOHDJaTJ45LjBgxpf/QoRIvfgL34QXgDl7me/HCBalTrYrkzV9AWrRt51eaHdu2yYghg6V5mzbyYY4nn+s6duSI8j537ieJ/UYcmfLZzACQCFiUpwrcrWtX6dU5Cz9a8QFL0vdYARG482fPlvatWsiytevk7XdSSNN6dWXlsqXS5pOO0ql7Dxk7crj069lTfr581fcMiMjuXd9KpTKlNa2adesFKg03Lrpy+bLUqlJJ8hYoKI2aNZdw4cK5cRuf04R31KjRpFqt2j5f6/+CmpUrSrNWrVX0BTZ43YNLhzl/9iyp16ixHDl8WCqVKSVjJk2W4qVK+xX50sWLkjtrFrXnNGnTStN69WTY2HGSLXv2wGIJ0uu8LnBpv0sXLpQe/frL+NGjZOzwYbJ5x84nVmoypU4pxf4/9x59+wUpn6BIzKvii7IFlK/Dwemvt+/e+4QzIShYBTYNrzLu0bmTrFq2VMqUr6Bj0A8nT0ij2rVk/dZtfkXNkCK59g3V69SV/AULBRaBq9d5WYBR8OVLFsuUCeNlzKQpwoRh1qfTZeWGjZI02dvKBQE8c/o0yfj++xInbjzJmCqFNGrewjP9hVf5bvh8nTSsVVNwIFSqVk35OrxrV6msf0+bPUdKlin7iP2hbyaPuTanNwAAIABJREFUHycVqlSVI4cPSYOaNWTQ8JFSoUqVILHTpwrcK5cu/T/2zgIsi6br4387wcLCbuxufezALhS7AEEQsCWkBBGRFEXB7kIR7ASxC8XuxkAFlLD9vnN8b15QfOTGe2V9mXNdz/UIzM7s/nd29zdnzsxB1NMnUC9UmONu8+TNh+w5cqikwdQqSQvgKgTcErwDnz59gp2lJc6ePsUjBYIsEwM9dO/VG6P19HkkvH71KgBZoKaujoIFC8JjwUL806QRatWugzkenphmbgYSV6NoUegMHoKli31xPCwMzVq2xFgDQ/QZMIBP9dPHj9i+dStWLVuKL1+/8O+pDgJsFw9PZMueHRaTJ7FXuVTp0pgwaTLIU3zh/DkUL1ESngt9eXQSHf0aLu6eCNr2rS7qAKtXLMe6lSsweMRIbFizGnqGRvjy9Ss2r1uHhk0aw83bB2OGDcWJY0e5fvJef/nyBU62tvj85TOeP33KL0CCI7r+9p06s6fXfMpUhBw6iAN79yIxMQHlyldgoFq3ejVcnWZBd/gIBG3dinYdO8DLdzFePH/Oejx/9gw5c+XE0tVr+QU72cSEww9Y79mz0bxlK2TJkgWfP3/m9vQMx6Nh48YcOmFnaYG7d+7w8XM9vbFv9068jHqJ40fDkD1bNnTr2Quhhw8jMSEBzVu1xFRLK/auzfdwR6FChTBs1Oh09y+5A27yC3vy+DHaNWsCR9d5GDj424NPRv3CzMgQYWfOAfjKgNuxa1eYmE9Mty6qPFDugKu4Vno+Nq1bC0cbG+w9EsbPpMIoPGnkoIGwdpiFalrVuW/XrltXlTL9Vl1yha/kF/Vv+irKESTQDBe9L1es+7ZgWS4mV40JcPOrqSFoawAWLV/Bs2LJAZe+J8v8/NB/4EDsDAqCk6urJOthfvc+yRXAFNe1btVKLF7gA5tZTggLPYx9u3eDmCI1D23c27doVrcOeg/oD6e5835XGpUcL1d9aQaCZpvnzLJHqzZtkgB3w5o1uBxxkVnEwtb2B8BNLsq9u3fQunEj2MxyhMF4Y5XolSrgHt6xHYtnO6BEmbIcd6tRoiTH4ZapVBnFS5Xmf6vS0gK4NKUwevBgrN68GQf37eORVsCmjejVrx+at2yNBZ7uWLM5ADExMRgzdDCmWlqjXYcOaFK7JoaMHMUA1bNTR0yzsuIPm72VJfaEHEny8LjOdsLSRb44felKipjSmzduYPzY0TA2n4Te/fqxJ45eRHR80L4D2LE98D8jQn+eirO1nIHrV6/Bx98f169eRdGixWBvbcUgaDp5CqymTeXpJwLcEYN0GCrnL/Jjr1Po4UPYHBSME8eOIXjbNqzfug3h587B3tqSyxcrURz9u2ljzDhDhs3+PbrBca4rNDQ0GIhmu7mhR+8+DOTL/BbBY4Ev7t+9m3T8Yp/5PMW1dnMAdgYHscfg2PkLmOc8G7du3oC372I8evQQz54+hYeLC4aMGIEu3bqzZ5tGVDRlnjVrVkRHR2O6uRlsHJ1Yv7UrV+LZ00i+Prq2+Ph4hB46iEP792P52vV8XT4eHliwZCny5s3L2tk6zeZjt2zcgHt37jDwptf+JsAlkKUwBBpwJA+lUcxAnLp4iT9uNICoWbsOP+xysL8BcHcGbcfF8HCcPXUK9Ro0wFQra+TJkydJvhVL/DFz+jT0H/Rtd5jTJ45j1abNqFylqhwkhlzhSyHOr/RVlDsWdoQdAG4+C9C+YydZaKs4CblqTIBbrnx55MuXD2dPn8aw0aMxhcO3vnlw5zo5oXzFCvinbTvYzJjOfbtKVXn02+Q3WK4ApjjHRw8fwnLKZFy5FIGnkZHsNBo7zihFH71/7y52BQXh1s2boL5MnkdyasnB5K5vvWpVUgAuaUaOSOKTXwEuORldHB2ZTxo3a6YSuVMF3JhXr3DryiVE3r+HiDOncHz/HuTOmw+58+RhyJ27SrWj8rQAriKEwHuxH7xc5zJwes2bC83SpTmWsYiGBqZbWcPPdyEO7N3DQEjxiy0b1GMQK12mLPRGDMPaLQHImiUrA0ShwoUxfPRY9Bs4EBONx+Ptmzf89+RGHsad2wO5vspVq7L3klzqBKCrN22GyTh9ZEEWBtpPHz+hdeOGGDvOMAnYnj97in7du3Fc74BBumjfohmaNm8BY3NzdG3bFj379MFUKyvuAORNdvOeD/e5Lrh6+TLm+/lj6eJFOBoSAh//JdwmAXSNWrX5FKvXrMlTJ4EBW+C3wAfBBw5CLb8aLKdOAcXLkdeXRlXde/Xi+N1enTuhWnUtHgjQ9ZLn1t1nAXp17ohxJhM4NIMAluojD0yt2rX5Z/KCu3h4oXyFCtzu40cPQS9kB2cXhmuC83IVKqBP/29ebzICtvj4BEyztELIwQPY///eZFog9/5dIgPeeLOJqKalxZ5LiqcmD3t6TW6Am5iYCC+3eThxNAz586th0vTpHIJx+uRJGOuPRa++fXkAljy+VgCucnc/NjYWE42NePaAAJUGV+/fveM+TYOr3Tt2YPGKlahZ+9uzQkaA6+I4C4G79/LPfbS7YOYsxz+yUDQtVycn+EqPvnSNHz9+wAJPTx74r98WyAN8OZmcNE6uiwJwaQqX3o9NmjXj9SIEuOQEsZo2BZa29ihWrBi/e8lLlvx9KxeN5QZgVy5dguXUySwPDWwrVa6M2XZ20O7RAwu8PFGzVm14L16cwoNL0+w3b1zHh/cf2AllYDIBZpOnpBgsZ5TectGXGIEcW58/f2Kv7MixeixJegGXGGCyqQn6DtDBjJk2yKGiiIFfZjJ79ughVni4wmzWHNy7eR23r1xGr2EjVXp/0wK4NGVOHtg27dvj9atXDJxjhg0Bvn5F1Iso9og1atoUDjOteXRGf6epnNn2tuwJPXn8OGbb2yXF6H79+pWBj2CNXiI/85glr4+C/8lzbGMxg6/fwXkOhz306NMHdk7OePzoEVo2rJ8ihuThgwfo1r4tnx8tDOjRqSMsbW3RrEVL9ox6L1rMIQTUPn2k23XshInjjVChUiWGZHMjQxAwEeDSYrNN69ch/NqNJP1pRwfyPlN4AIVDkJmPN0L9Bg1g+J+YXQorUOhHI/8evXonXS+FRRDgkkdVERO6fvVq9lTTyJUGAWRUh8IomNzOygJWdg4oVrw4A66GRlGOvVHYvwEuebSNzSYyoO8M3o4zJ0+yfuk1uQEuXQf1L4WRdt9ibJvxIIFivr635DGLihCQnn37wsBINVM16dVWcZwcPbjfa6w4V/Lg0vM01tCI454VRoBL7wB6HxQsVOg/MzrWsom5lxt8Kasv6Rz14jn6ddPGwCHDYGQqnzUDij4gN40V56UAXJolo/C6TevWISrqBY6ePY+Qgwe5P9PMmuLdMnHadP4+pHeB7+++D352vFwALPn5Je/H4/XGIDEhkb/HNDur06sHh4T8LKbZcMxoPHn8iHmCPOwZbXLSN7X3Q3oAl9aoUP8uVboMFi1brlKJUwXct7ExiI6KQt78+fEmJgab/H0xw0263QLSAriKRTgEt0T4FOtKnXXz+vXoq6ODuZ5e7Mn1W7gAWzZs4BgOWrn3JjYGISdP8wg46vkL+C5bDjcXZ+7QBK80CqYAZ5pSK1q8GKZYWLLnU2HkrSXYG29mjpPHj2GMgSEmTzBmGOzYpQs6tmoJ9/k+vDiAwI9gtm2HjgzbBDZU1+ghutAfb4yL58/j8IH9WLZuAx7cu8ue1nNXrnHcLHmjfJetQOkypdFHuyt7fClGkxYeNW7ajK9vzYoVcJhpBU/fRShYoCBKlSnDH+oJBvqoUasWJk2b/i1e1toK8XFx0Bk8GHly50HFypV42stYXw9B+/ZTiCd3qGnWM9G4SVMOdSA96tSrj7t3bqOqVnWGZnqBUnxsYQ0Nng7Lli0by0LATXrNsLHl31NsI8XakJYU11ygUEHcvnnjpx7c5IBLXgo659+JuZEj4CZ/ShUxieTRXbpmHf+pSFENVK5cBcXU8vHAgBaWjB4yGE2at0CJkiXBq6o3b+Y4bjmYHAE3uS7Uv8PPnWWPDMV9k4eBnqcCBQqAFufQB4qe1/7du6Fzt258KHkNNpCX8f+9YnIwucIXaZMWfakfU+iT7YwZPKNFg3i5mVw1Tg645LGl78G1K1dwKuIyFs335m+JockE5MiZk2eC6Ds3x80NGjLzkMsJwFLre3McHBB2JATGZua4ef06dmzfjgVLlmC+uxvIsfPo5WtsC9iCAgUKonDhwjAaO5o9v/QtTB7ulFH9Wq76Umjiw/sPmHVq16vH3zN6F0dGRuLgvr28DmnoqFG8wwL1WeKP0qXLYN58H8ycMQ3hZ8/xDK86rZkqXIi5SRVe3FQB99i+3VjhOQ+FixZH3nz5EPU0EgP0DDn+VrNsWRQoXESl9zctgEt7zi739+MQAZrqp/hN6pw3rl1F67Ztk+IZabsv2k6MYj0rVakCGh1QyADFj+XIngNde/TA8bAjHOdKRqKSF5T+Th2e4h579O6ddH0UtkCeH2qfPpBaNWrygjCKn6SQAlrQQquyaeqDLPTQIQZh+huFBZBReQL03v3748CePRgyciRu37yJsJAQXjV/4/o1HqUr9tRdt3oV2nbogJKapVCzYnn2FNPInoymWBVGH5AmzZvzx7xipUoMwhRSQPVRDBFdV86cOdGpqzYfsn/PbtYiLu4te7dpe5SSmpo/6EFxzLuCtoPilciqamnxAj6qS2H0Qm7ctCn/Prl+FJ9M50qB5R8/fuRtQSgO+M7t2zytRjBLIQukH4HF9EkT0bFz56RzTE/Hkjvg0sCH9jFWeGDoGrWq1+C+6Ok6l1dGk47h589h365dLAHdf8X9TI8mqj5G7oBL10vvA5q9Sa4fPb/0PqBFjrSgjEKdaMEDGT2PdB/kYnKFL4U+adGX3n/k8erWqzcv7pWbyVVjeifSDF/9ho1YMvqZthYcYzAOZ06dhKZmKZSvWJH/Rmsc6P3cWbub7LYLkyuAKfph8u85/Y4Gu/UbNOTv/+WICOYB+l7Rz3Fxcbzehr5nxBNyMLnqS1tcEs/Q951MwT80m0Y8pDBa/zR4+Ajuv7QLU7tOnZL4SFGGWIbeHxSP/rv2k10UonDx5HHcv3UTD27dxO2rl/E2NpYzmpWrUgVOS2iHAtVZWgBXda39PTWFhYZCb/hQbAzcjnoNGsrqxA8d2M/btHn4pD92lsCvX3dt7Dp4mON802tyB9z0XpecjvsbAFdOeqXnXOQKX+m5FrkeIzSW9s7IFcCkveo/V7vQVzmt/zUGNynG4utXvIh8gusXLyDm9Wv0Hv7nY3CVu6y/vzRN41Nsq+nESbC0s5flBdXXqsbxpN8nzUjrya5YugSRjx7D0s4urYekWk4A7m/Jl6aDBeCmSabfKiTg67fkS9PBQuM0yZTuQgLA0i1dmg4U+qZJpqRCqQLuwzu3sXfLRgwyGI/cefOyB1e9YCHeE5f+T3u/qtKEB1eVama+ugTgSn/PBeBKr7GAL6Gx9ApI24IAMKGvtAooV/tP98F9dPcOdMcZ43XUC+hrt0eZipWhUaIEuusOQ9N2HZRr5RelBeCqVM5MV5kAXOlvuQBc6TUWgCs0ll4BaVsQgCv0lVYB5WpPFXD3bN6AL58/Q3vQEDx/8hjullOhraOLI3t24cP7dyIGVzmNRWmJFRCAK7HAAATgSq+xAFyhsfQKSNuCAFyhr7QKKFd7qoB7/MA+XL9wHkPGm+JdYiJCdwah94jReBsTA/3uHbHh2FnlWhEeXJXqJSpLqYAAXOl7hABc6TUWgCs0ll4BaVsQgCv0lVYB5WpPFXCf3L8PH3trNGjRCi27aCP/f1a437p8iVP4+u36caN65ZpNWVqEKPyOeuJYAbjS9wEBuNJrLABXaCy9AtK2IABX6CutAsrVnirg0l6zZ0IPY4nrbOTKnQcly5TlWq+eP4shxqboMfi/GauUay710gJwVaFi5q1DAK70914ArvQaC8AVGkuvgLQtCMAV+kqrgHK1/3SbMIrBfXDnFsKPHcXd69e4Vq169dG+Z2/kza+mXCu/KC0AV6VyZrrKBOBKf8sF4EqvsQBcobH0CkjbggBcoa+0CihXe6qAe+7oEezfuhnV6tZHjfoNULVWnW+1ZsnCKQNVbQJwVa1o5qpPAK7091sArvQaC8AVGkuvgLQtCMAV+kqrgHK1pw64YaFY7j4Xb2JjkBAXh69fvqBs5SqoVL0majdqgjbdeyrXivDgqlQvUVlKBQTgSt8jBOBKr7EAXKGx9ApI24IAXKGvtAooV3uqgPvh3TvEvX2DN9HRnMHs8f27eHzvLl49f4YcOXPB2ttXuVbSALgVCuTD569fVVqvqCxzKJAtSxYEBwfj/IULmeOCM+Aq+/fpjUMhoYiOicmA1jNHk1PMzTDP0ytzXGwGXaXQWFrhCxUsiPZt2yAgcLu0DWXS2oW+yt34VAH35MH9XEuzDp2Savvw/j3i377Fp08fUbRESeVaSQPgllPPi49fBOCqVNhMUlmOrFlw5epVPHz8JJNc8Z+/zIZ1auPa7dtISEj8841nkha7tGuDvYdDM8nVZsxlCo2l1T1v3jyoXrkyzkVckrahTFq70Fe5G//TRA9UTVcdXfbgbli8AKb2s7lmHztrmNg5KtdKGgC3tFoevP/8RaX1isoyhwIiREH6+yxCFKTXWIQoCI2lV0DaFkSIgtBXWgWUq/2ngBvz6iU69dPhMIWNfgsxw82ba9Zt0RAbjp9TrhUBuCrVS1SWUgEBuNL3CAG40mssAFdoLL0C0rYgAFfoK60CytWeKuDu27oZq7zcUKZiZeTNnw/PnzzBQAMjFNMsBTvDsQJwldNYlJZYAQG4EgssUvVKLzAAAbjSyyw0llZjAbhCX2kVUK72VAH3ddQLXDh+DA9u38SD27dw5+oVXnSmVqAAKBZXeHCVE1mUllYBAbjS6ku1Cw+u9BoL+BIaS6+AtC0IwBX6SquAcrWnCrjPHj1EYnw8bw1G+95++foFL548wY2IC4iNjkafEaOVa+UXpcU+uCqVM9NVJgBX+lsuAFd6jQXgCo2lV0DaFgTgCn2lVUC52lMF3LA9O+FjNxP1W7ZC1wGDGHQLFi6CrNmyKVd7GksLwE2jUKJYqgoIwJW+YwjAlV5jAbhCY+kVkLYFAbhCX2kVUK72VAH3bWwMzh8Lw+nQw7h9+RKKlCiB1l26oVGrNiiqqalcC2koLQA3DSKJIj9VQACu9J1DAK70GgvAFRpLr4C0LQjAFfpKq4BytacKuIoqaN/bx/fu4MyRUJw8tB+fP39CG+2e0DU0Vq6VX5QWgKtSOTNdZQJwpb/lAnCl11gArtBYegWkbUEArtBXWgWUqz1VwL138zpOhxxGYnwcbkZcwJevXxH/5g2uR1yARomSWH/0jHKtyBhwP336BL+FC6ChoYGBQ4aibrUq2LZrNypWqpyma4x+/Ro+nh7Q0R0MrRo1fnlMyYLqXGamwyx079UbOr164HTE5V8eJwr8XAEBuNL3DgG40mssAFdoLL0C0rYgAFfoK60CytWeKuAeDg7EnMmm+PTxIzSKl0BBjaIoW6kyx+FSiMJAfSPlWlEB4H78+BGNa9XA58+foVG0KO7dvYv1W7ehafMWWLl0CaaYTuBWnsa+Rc6cOfHu3TvoDR+K3Tt2oLO2Nnz8liBg00a4u8zBluCdqFWnDpePiY6Gl9s89NPRQe269VCjQjkE7z+ASpWrpOkaL0dEYJGPN1w9vZEnb940HXP71i2EhYZAZ5AurKZNQV+dgWjbvkOajhWFflTgbwDcxw8fYqnfYizzW4y5Hl4YNHRoiguh/urmMgfBW7cie47sKFO2HFy9vFC6TFlZ3HI5A+7Bffsw0dgIjnPnoVffvoh68QJ2VhawsnOAZqlSrJ+/78KkZ79m7dqy0PT7k5A74F6/epXfleFnz8LH3x+NmjT9Qccjhw/DxWkWPn/6xH/bE3JEVlrLVWOvea7wdJ2Lrbv2oH7Dhrhz+xaMxozGviNHk/SbPMEER4+EYtP2YJQrX15WuipO5m8A3Li4OEw1M8WWDesxcdp0WNraJWn59etXXAw/D4eZ1nj75g1iYmJg6zgb2j16IJtEa5CUuZFy15f0W7NiOetXvkIF5MyZi9lqrGFKZvzV91AZTf6tbKqAS9nL9m7ZiGsXwnkXhdpNmqJR6zaoUK26JDc5LSEKd27fRs9OHTDFwhJdu/eAib4eipcoAfcFC+FkZ4sdgdvw/NkzhJ4+g6rVtLB9awBcZzuBOnObdu3h6umFiSbG3Hn3hoYhX758rMu1q1ewwMMDLh6eyJc/fxLgfnj/ATdvXEfvfv1x++ZN7Nu9Cx8+fED27NnRvFVrNGzcmI+fZTOTYblthw7Yu3MXSpcti7OnTqJxs2bImzcfQg8dRPmKFRmy6ed3iYkIDAhAsRLF8U/bdtizcwfOnzkDG0cnVd3TTFeP3AGX+s30ieZ4/OgRTp88kSrgXrl8Cf27d4On7yKULKkJEwM97uvU/+Rgcgbc4MBtWLpoET+fGwO38+A2OeAmJMTD1tKCn/n3797D2c1dDpL+cA5yhS860YSEBHRt+w+KFiuGJ48epwq4z589RadWrTBt5kwMGzlKaKyEAnZWlrh14zqyZMkKv5Wr8DTySQrAjY5+jSH9+uKfdu1QomQpjNbXV6L2P1dU7gD25csX0Pti766d2B0cDP3xxikANzExkXmCHGk2DrPg4uSIa1euwMfPn/t+Rpvc9aUZcd/53gg/dw6eC32hrv5txjq5peV7qCqdfxqDSx7T1y9e4Mq5MwjbuwuRD+6jTMVK6DdaDzXqN1RV+1xPWgCXOqWp4TjsPhSCuLi3DLhTLK3QqUtXGI0dg9JlyjDUzp7nhtZt2mKi8Xi0+ucfzPdwh/748RhrYIiOrVqgVt26WLZmXdL579u9myHUyXUe/448uAuWLMW2zZvQd8BANGraFPPd3VCseHG8fv0au7YHYtWmLShbrhxeRkWhX3dt7Nh/EFFRL6DTswf6D9JFqTJlsHN7ICpUrMQvJPIwDR05kj0eSxb58t/pHPPnz49bN25gjqMDe5jz5MmjUl0zS2VyB1x6WV69chmvXr7ESN1BqQLuo4cPGSDIM1OrTl2cPH4MS1evRZVq1WRxG+UOuCePH8ezp5GoXqMmRo7VSwG4ly9FYHtAAIaPHoN+3bryDE3J/09aIzeTM+DSR+nMqZOIfPIEbs7OqQIuzZAZ6+uhTr16KKBeANVr1YKD8xxZySxXjQlwS5QsieNhYejdvz/qNWiQAnBpJvLM6ZMYMFAX8+bMhofPQhQoWFBW2tLJyB3A3rx5g1kzrVGtenV4zHXB0JGjUgAuvaOH9O+LHn36wmiCKbZt2Qz//w9hpO9zVS2tDNdb7vqmBXDT8j1UldA/3UXhyb17+PTpI7dDJ0Sgu8bHE4U0imLtkVOqaj/NgLvQyxNO9nb48vkzyA0+ZMRIOMxxQWJCAkYM0oGRqRlsLGZg0JChqFipEsfFevkuZuj0Xb6cQw7YA2xphTH6Bknnv3rFcsTGxMDEfCL/rnwxDbRp3wH9dAaiV79+DLGuzk4wNjXnbdJ6demE8Gs3uOyqZUvx8MEDWNs78JRSz04dcenWHbx6/Qom+vpw8fCApmYpHtFUrlIV9Rs1Qn2tqsiaNStq1KqFjYFBoIGEk50N7JycZTFCVOmN/UOVyR1wFTKEnzuLPtpdUwVc6tPUF0oWUOP+MWHSZEy3skau3Ln/kIr/3ozcAffcmTOYNH0Gmteri2Vr1/KzqQhR2LBmDYctGJmasie9WYsW0Bk8RBa6Jj8JucJX8nMkJ4KzvX2qgLtiiT9m29th1cZNfAgN5ub7+aNzV23ZaC1XjQlwaXBLoWqWUyfDfOo0zJw+LSlEwdTQAIOGDEP1mjVZ48HDh6Nh4yay0VVxInIHMHIckH42s5wweoguBg8fkQJwo148R99u2hg0dBgD7s6g7fB2m8eAS9pntMldXwXgUohCjuzZUbBQIX4HdOjU+Qfp/u17qCqdUwXckB3bsXCWLU+XIAuQM1duZMv+bQ/cEqXLYM6K/3pAVXEiv/LgEmCbGOjjxfNnCNixC+fPnuUpXPqg1WvQEDo9u3MHpBHZu/fvoKamjs7duvGUpM2M6dgcvAOPHz6Csf5YrFi/gUMDFEZxTzly5oCx2TfALaGen+HTZOIknh5+ExvL4NykWXPExsbg5vXr8F60mKdBe3XumDSyUwDu1XsP+GNK5+fqNZ/DKChUggCbXkrfG3lE6BxtnWajTFl5xFuq4p7+yTrkBrg06Jo3xxlHQ0OQX00d061nokmzZvi3BzriQjh0evXEiDFjOQaP+jvNKgwe9mOf+ZPaKtr6GwB3mqUVNqxdg4gLFxAf9xb2zi5QU1fn54vgoVWbNjzL8+L5C55yzJEjR0ZI+dM25QRfFHtorDcWL6NeoEo1LUyxsED5ChVZv38DXBfHWQjcs5dDuWjAP83KGqP05DOdLieNk3cEBeDSQmf6JuXKlYvD1w4cPc7fHOvpUzHGYBzyq6nBf+FCtO3QESPHjuXBsJxMbgB26eJFTDE1YYkIWo8cPoQ8efKiv64u928Kd7S0tUXxEiW5DM3EDuzVE/0GDmLADQzYgsU+Pjygq6ZVPcOllpu+xGZbN2/CEt+FrI3p5Cm8eF5huv36cDw+8RmxUHLLMMB9+ewZHt69jWxZsyFL1iwoULgwcuX+Nn2eX70A8qcSV/E7d/5XgPsNGPV5BGXnNBshhw5impkZ5nh4IO7tW5B3lwT0X7QQS3x90bptW/55gZcHwkJCOOZ25RJ/9gATgBYoUCDpdCnQnBasTbW04t9RiILTXFfs3b2LvbrU8aeZm3FYAS1eM5sylY8nj5GDtRW2793Hx6UXcJ88egT7mVYcA1yoUOHfkTHTHis3wP11V7T7AAAgAElEQVTZjUjtgabFJTSVG/3qNaZNNMP+sKPIn1+NB0it/mnDgzg52N8CuPEJ8Ty1+zQyEpuDdvD7wcxoHOo2aMAx8Anx8Xj86CHsZs9B5SppW0j6p/SXK3wlv/7vAZccAMv9/dBJWxsvnj3H2OFDsXj5Sg63GjVEF/4rV/P6BLmYXDVWAO5ofQMcCTnMYSBPn0bi5IUIBGzciE3r16JGzVrIlj07Ht6/jyJFNXgnHnpXyMnkBmDfa0Pv29jYWJ75Xbd6FYfT0CKzt2/f4trlyxgzzhDTzExRpGhRWNnZw9ZyBiIfP2aeIG9kRpvc9aVZyLt37qBkyZJQL1AAw3T689oI0o+84WTUx8kyDHD/9E38FeCSd4sAl8QrU6Yse2m7aHeDnqERe1fpg0UCblq/jgPEnee5c8xru+ZNUaFSJSzwX4pJJuNx5dIlHDl9NsXl0arfwIDNcPf5NgIhwA3cvRcUt0cv7vUB2zDPeTYiLl5A9mzZUbR4Ma6PHhR6CBSLKdILuOSNpm3KFvj588tLmPIKyB1waeECDcL279mD8+fOopqWFntqR4weA81CBdizT2Euun37IHfuPOxZLFCoIGwcHGUR90V35G8BXArpWLtyBTxc5mDnoRCcOHaUP1zTrGfyADU+Lg5O9ra8+4pcFvAperxc4YvOj0CWBmC0kwIt+CXYMp86FTVr1+GwK3r/9tXRgZ2lBY6Ffds5gTw5NNWeWyZhNnROctU4OeDS+8Jq6hReG3L0XDiHuFWoWJH7K3ls7929g5nTp2Oupyc0S5VW/oUp4RFyBzDFpVPoIfGBIkSBHArrV69GVHwiQg8f4gEGvS+ILbwX+6FZi5YSqpb2quWuL3l0jx8Nw5oVKxD96hWuX7sK36XLOSysUa1v26geD7/40++hqkPy/jXRQ9pl/72SvwJcWvlIW5bRfrxktLMDQQA97AS9ZPQziUsxIIq/vX//nsvQz1SO4hyp0ya3J48fc0yO/ezZ0ChaDHQMlVHERL54/py3FJnnPZ+3J6MXT+WqVXHlUgQsbOxQqvS3FwyVp5EKTS3Rv+l8s+fIwedK50T/T22bEdpSg7Yqo5AIYelTQO6AS1dF/Y/6p8KyZ8vG/YNCXahfUB+l/kN9nYx+x/0nfZKo/Cg5Ay7F5dO7gabFyehnfg/kzPlNz69fUwwe/+15VLlwSlQoV/hK/n6jd5vCkr9n6d/UZ6mPJ38ny2FrpeS3QK4af98n6Wfqxzlz5eK+TN8xRTjC998XJbqY5EXlDmAKARTfa37PZs+e9H6mwZji20/vDvpuEw/Q/+Vgf4O+yXktuX7EVmTESD/7Hqpa41QB9/7NG4h+GYWaDRvzAya1/QpwpWyfthEj71qLVq05Ru97u3D+PDznuUJvnCHy5M3DOyq06/gtYHqArm7SdmPpOUcCGnLhOzi7pClJRHrayAzH/A2A+7ffBzkD7t+ureL85Qpf/yv60nUIjaW9m38DgEmrgLS1C32V0zdVwKVtwZbPc0Hbnr3RQ3cYCku8/1tGAi6NNk4eO4a8+fLx1izf2/t373jfvCuXv2Ubq1u/Pvr0H6Ccyj8pTbs30MpjiusVln4FBOCmX7u0HikAN61Kpb+cgK/0a5fWI4XGaVUqfeUEgKVPt7QeJfRNq1LfyqUKuG9iYnBs325sWeqHQhoaGGZijlqNmvCUqRSWkYArxfWIOv+sAgJwpddbAK70Ggv4EhpLr4C0LQgAE/pKq4Bytf80Bvfrly+IefUKPg7WOBMaggYtW6Fei9Zo0KIVp+1VpQnAVaWama8uAbjS33MBuNJrLABXaCy9AtK2IABX6CutAsrVnirgRj58gF0b1uLovt14Ex3N24Rly5YdiQnxKFikCBZs26VcK78oLQBXpXJmusoE4Ep/ywXgSq+xAFyhsfQKSNuCAFyhr7QKKFd7qoB7OuQQdm5Yi8o1aqJyzVqoWrsuZ1SKiozk/eNqNPjzqXqVuyxROjMpIABX+rstAFd6jQXgCo2lV0DaFgTgCn2lVUC52lMF3IT4OHx49w4FChVGlj+QKUV4cJW7aaJ0SgUE4ErfIwTgSq+xAFyhsfQKSNuCAFyhr7QKKFf7T2NwT4cexgr3uXh45zbqNmuBnkOGo/E/bSVJRiAAV7mbJkoLwP3TfUAArvSKC8AVGkuvgLQtCMAV+kqrgHK1pwq4NyIuwNvGksMRcubKyZvyRke9QJf+gzDSfApy582rXCu/KE2AW6VQfnz57x7iKq1fVPa/rUDWLIC9gwOCg3f8b19oBl6dvZ0tFvv5ITLyaQaexf920zuCtqNHsjzu/9tXmzFXJzSWVndNzZIYZ2AAWzt7aRvKpLULfZW78akC7sGgbbh6/ixGmE7mBWbxb9/g4skTWD3fA72Hj0JXHV3lWkkD4JZWy4P3n79lcRImFFBGARGioIxa6SsrPLjp002Zo4QHVxm10ldWaJw+3dJ6lPDgplWp9JUT+iqnW6qAu2fzBk652G3QkBQp6i6cOIaVnm7w2LhVuVYE4KpUL1FZSgUE4ErfIwTgSq+xgC+hsfQKSNuCADChr7QKKFf7TwF36Txn1GncDLWbNEO9Zi1QqnwFTvQwuFVjbDh2VrlWBOCqVC9RmQDcP90HBOBKr7gAXKGx9ApI24IAXKGvtAooV3uqgHvrcgTW+/rg4d3bSIyPR2J8HLJkycoJHp4+eogNx88p14oAXJXqJSoTgPun+4AAXOkVF4ArNJZeAWlbEIAr9JVWAeVq/+kuClRN3JtYRD19isiH9/Hg1i08e/yQvbim9rOVa0UArkr1EpUJwP3TfUAArvSKC8AVGkuvgLQtCMAV+kqrgHK1pwq4nz59RPixozi4fRsS4t+iZoPGqN+yFcpUrITPnz4jv7q6cq38jwDupvXrcPjAAdg4OqJkSc10aRD39i0857miStWq6DdwEHLkyJGuei6cP4eL4eEYOVYvXcc/fRoJXy8vOMxxSdfxcjpIxOBKfzcE4EqvsQBcobH0CkjbggBcoa+0CihXe6qAe+3CebhOm4h7N67j69evvPdtPjU16E+3Qs8hI5RrIQ2l07oPbosG9fD40aOkGo+fD0e+/GowGjMaDRo1gtmUqUhISOCfCxcpDBd3Tz53R1sbPsba3gF5f2OLMxMDPRw9cgTnr15H1jQmwHj75g2mTzJHwUKFuf34uDj0664NwwmmGDpiZBrUSb3ILJuZqNegPnr26ccF/BYuwDzn2Xj37h1q160H9/k+qFa9Ol5GvcDg/v1w49o1Ltd/4CB4LFiIL1++oHeXznB0dUXdevXTfR5yOFAArvR3QQCu9BoLwBUaS6+AtC0IwBX6SquAcrWnCrgHAgMYbkeYTUbOnDkR+fABwnbvROCa5Zjk5Iombdsr18ovSqcFcCOfPEGn1q1gMH48ez4JNjU1S2G2mxv0RwxHvQYNMdXSCocPHsDQ/v3Qum1bLF+7HjEx0Rg5aBAmz7BA7/79+UzIQ/3w/gPkzpMHL6OiULpMGeTLnw+3bt7Ep48fkT+/GsqWK4ecuXIhKuoFnjx6hPxqauir3RUdOneGk6sbHj64jzJlyyF37ty4f+8u1NULoGixYoiPj8ftmzeQPXsOVKuuhaOhoZhqZopO2t1gNnkK1/Pg3j2uX01dHbdv3kRc3Fs+r8pVqyFfvnyIevECCQnxeP/uPd69S0TRYsWhWapUkopPIyPhMssBM2xsUax4cWxevw7HwsLg6DIX6gUKYGfQdixdtAh+K1fh69cvsLe2grHZRFSvWRN9unbGuAmm0O7eAxvXrUVEeDicXOep9H7+6coE4EqvuABc6TUWgCs0ll4BaVsQgCv0lVYB5WpPFXD3bd2MuNgY9B4xBtmyZUuq8eje3dixbjXmrFynXCsqANyD+/bCYNRIbAzcjvz588PYQB99+vXHSD19mI83QsVKlRhwR+gOxP07d1GylCYD7qplS9nr6uPnj+IlSvCZPI18AmN9fZQoWZLBsUOnzrh54zoCAwJQqXJlRFwIh73zHJTU1ISTnS0+vP+AXLlyYVdwEP++cpWqDK3L161nwBzctw9GjB2L3v0HYK6TI27duAGNohoYoz8Oi3zmY9+e3ejQqRPGmUxAfFw8LKZM4vMh7y55Ylu3bYdD+/dBR3cwjM3M4eXuhuBtW/n3Z06dRDUtLcxx90zyPkdcuIDtWwMwYdIkZM2aDS6ODujQuQvad+zE1xcXF8cDABPzSShXvlwKwDXW10NnbW307tcf169dg9HoUTh88pRK7+efrkwArvSKC8CVXmMBuEJj6RWQtgUBuEJfaRVQrvZUAff8sTDs3LCWPbjlKldJqjEuNhZ62u0zZBcFf9+FDGpNmjVjSCxesgRcPDyhrqYOy6mT2ctJYQpTTCdgyIhROLR/LxYuXY7hAwdgjL4BjEzNkq6DAJEAUGfwYEyYOBnnzpyG5ZTJsHd2QfkK5dGrS2dY2tgi4uIFbFq/HoePn8ThA/sx1dyMAfvRgwfwmOuCbbv34uOHD+jWoR3cfRYgMjISzvZ22LZrD4poaHAGOIJlCpEgoCUvM8Xfhh48CPNp07hNAlMH5zn879DDh7A3NAwWkyfixfPn8PRdBP+FC3HlUgR8/Jawh5gsLDQEJ48dw3hTM3z48AHuLnMwcOhQ1K5TN+ka6fo6ddVGi1atMGqwLrJly87e4249e6JLt+5cV2JiIprWqYWjZ8+z5/dvNQG40t85AbjSaywAV2gsvQLStiAAV+grrQLK1Z4q4L5PTITXTAsc3rkdHXv3Q52mzaFRvAR2b1qPZ48fwXtLkHKtqMCDa2o4Drdv3cSmwCCcP3cWFpMmwdLODu06dISNxQwULFQIJ46GoXTZsujeszcWenuis3Y3LPNbjIPHTiR5b+lUdm7fzoBLnsvSZcpi8QIf2FlaIE+ePHym3Xv3hp2TM7q0ac3hEDazHOE73wtOtra49TgSHq5zcfPGDXj7LsKRkMNwc5nDADpKdxCKlyiO4P0HkxJkONrZIiL8PP+dvL3j9cZwGEObdh3gYG2JgJ270LBxE0wYp4+wkBDsDzuG/j26YcAgXQZYU6NxXBcdT/8n27E9kKF8qoUV3r9/j9kO9hg0ZCgaNWmSAnAHDx+JqtWqwsbCAnqGhjh7+jT2796NLTt2JpWrUaEcduw/iIqVK6v0nv7JygTgSq+2AFzpNRaAKzSWXgFpWxCAK/SVVgHlav/pNmFvY2OwyW8hwvbuRkJcHL5++YJcefJg2lwPBl5V2q9icGNiYmCir8eQ6jbfB+fOnIH5eENMmDgJffoPYMA8uG8f7t25jV2HQnDn9i24zXHGtStXYGVnD2PziUmnS4vmVi5dgjUrlmPDtu0Mxr7zvXH21CnMX+yX5Mmk2Nx2zZti8PAR0DM0Ak3tf/78Cas3bYbVtKnIni07Zsy04fN6/+E9A2iPju0ZMn2XrcDrV69QuEgRjBs1krPC+fgv4XjmJrVrYvCw4ahctSomm05AyMnTvGCNgLthoyYYqTcWOj17YJbLXLTv1Dmp/PSZ3xbKkRFUnz5xAkampvwzhVFUr1ETQ0aM5LoIvn083DDTfhayZM2SIkSBFurNcfPAP+3asfe3Yc3qCDt9lnX4W00ArvR3TgCu9BoLwBUaS6+AtC0IwBX6SquAcrX/C+DG4n1iArJmy4bH9+/h88ePKFpSE6UrVFSuhTSU/hXgXr969duistKl0axFS9y8fp2n/53nuSFvvnwMqOSB7dGnD1au34iQgwdgYqDPHs89IaEoVbpM0lnQtPxse1u8evkKcz08+fjgwG3sxaVY3Dx580Kreg00bd6cp/a/fP2CFq1aY+umTejYtQumW9vAYaY1Lp4/h87dumH3jh1c3tXLm8Mjjh8Nw/DRo1G4cBEM0B0M8jzfvH4NMx0cUapMaXRv3x6evr4MpMN0+qOTtjbeJb5DTHR0ErzTtfj4+yNv3nzo/E9rLk8xswq7GH4ewYGBDPgFChZE+LmzWDR/PrRq1ECOnDlx/+5d1G/YEDqDhyA2JjoF4K5dtRKkp43DLNy/dw9jhg1B2BnVJu5Iwy1XaREBuCqVM9XKBOBKr7EAXKGx9ApI24IAXKGvtAooV3uqgBv54D7W+Hji0d07qNe8JYcnnAo5iGbtOqLXsPRvbfWzU/sV4BL8Xbp4EfHxcVxFrty5UbtuXWhoFOVtzAjobly/huo1a6Fc+fJ4+TKKy9OWYE2bt0jRLHlTr1+7yr8jMKVFdG/fvsWlixfwJjaWf1+qdGneaosWi5E3uFDhIvx7WpRGux8o2itUuDCDLG25RVtyUdzs+bNneGuyOnXroniJkgzjd+/cRply5XjvXILROvXqcwwseWFfv37FdVN71O6zp0+5PP385fNnnD19Kqm84kKePH7EHmqCbcXCOTr/J48fcxE6X2qfYJ1CGAiwy1esBDU1Nbx+/Zp3cSD9grZtxYmjRxnO/2YTgCv93ROAK73GAnCFxtIrIG0LAnCFvtIqoFztqQLuoeBAbFuxFPWatcTBoK28kCqfmjqeP3mECXaz0W3QYOVa+UXpXwGuShv7H6iMoN7OygLNW7ZC1+490n1F/bppw8LWFo2bNkt3HXI4UACu9HdBAK70GgvAFRpLr4C0LQjAFfpKq4BytacKuHs2b8C7xAR0GzQUt69extblSzDDzRtXzp/FYudZWBi4S7lWBOCqVC+q7NSJ4zh94iRvFZYee/zoIZzt7bFgydL0HC6rYwTgSn87BOBKr7EAXKGx9ApI24IAXKGvtAooV/tPAXfH+tWo06Q58uTNh6vh52BkZYtCRYtCX7tDhmwTptxlidKZSQEBuNLfbQG40mssAFdoLL0C0rYgAFfoK60CytWeKuA+uHUTewM24f7N63hw+xZiX7+GZrnyyK+uDorP3XBctYuSRIiCcjdNlE6pgABc6XuEAFzpNRaAKzSWXgFpWxCAK/SVVgHlak8VcCnGkxZjffn0if//OuoFIk6fwrUL55EQ9xbW3r7KtfKL0gJwVSpnpqtMAK70t1wArvQaC8AVGkuvgLQtCMAV+kqrgHK1/3SbMOWq+b3SAnB/T7/MfrQAXOl7gABc6TUWgCs0ll4BaVsQgCv0lVYB5WrP1IC7fWsAIp88YcWKFCmCHn36cqKEfbt38ZZblESipKYmEhMScOL4MTRt1hz58udXTmFRWnIF5Ay47969S+pPtE3bsFGjU9WD9jY+ffIkJwGhlMpyMzkDLi2YPLR/P2cIVFNXx7CRo1KVL+7tW6xesZy36GvfsRMnYpGTyRFwaQaPtio8f/YsS0XJalq3aYuqWlpJ0iXXX/FLSpveqElT3oZRTiZHjUkf2k6SUrBT8h2t6tXRrmOnH2S7cvkyjhw+xL+nHXTq1KvH3ys5mZwB9/TJE5wkioyef9raM7kd2r8PN65fT/G7/gMHcQZSuZgc9X3z5g0OH9jPEin266d8A1s2rEdcXBwKFSrE/VmxpWlyLSmHAZmCv2hrV1VapgbcFvXrwtphFuuppqaOJs2b8z62m9at47S9TVu0QLeevRhQKJsadfbcuXOrUn9RlwoUkDPgUkrlkIMHUb1mTaxatpSTf1AaZoURQOzZuZN3xVi7cgVCT51B6TL/TUyiAnlUUoVcAZegdf2a1Qy2d27dxAr/JVi+fj1a/dPmh+v2nOeKzevWIneePJx5kO6JnEyO8EWDewcbazyLfIo+Awbwe7Fm7dopkudQ1seIC+GgwVxsTCzmODpwEpoxBuNkB2By1JhS0NtaWPD35tOnTwjaGsD9s1adOkndkwbAx8LCeK/0wC1bkJCQgMXLV8guA6UcAYxEPHokFFZTp2K0vj7OnDqFt29iMd/PHwUKFEymcThoj3myXcHBCNi4AdcfPOJkSnIxuekbGxsDW4sZ2BkUxAOz4P0HWSofD3ceGHz+/AU+nu4YOVYPo/UNkCNHjiQpKQMr5RWIfv2a3+GUdbZH7z4qlTrTAu69u3dgMHIE9ocdSyGoj6cHKlWpgnt37qBi5cooWrQYdgYFwtLWHtmzZ1ep+KIy1SggZ8ClDxYlAiHP15LFi3Dh3Fn+eCU3SsYRFfUCXdu04cx7AnDT3i9ovcCH9+85g9+jhw9BqajpRTne1CxFJfS89+7SGYYTJiBg40YBuGmUOCE+HjYWMxikplpaIVeuXP96JA3UzIwM4e27mB0GcjM5Au7OoO0MCYF79vE3pn+Pbhg6chQMxhsnfXM+ffyIz/QeyZUL61augKOtDQ4dP4GSmqVkJbHcAEwhzqyZ1ggM2IIzl6/i8IEDMB9viCWr1/yQCIrKx8fFwdRoHLIgC5eRk8lN30cPH8Bo7Bheq5U9W7YkwKWBMSXkIgcEaUkcZe/szNlZFUY6UzKqhw/uw0RfH81atoS1vYNK5c60gHvy+HE42s7k7GWUkYw+ipTwwNnBHpqlSuNoaAg6du2KPTt2YLKFBbvQS5TUlJ1HQqW94S+tTM6Aq5CUQNdiymRUqlSZIet7Iy9Yu+ZNsfuwAFxlu2F09Gs8fvQIQdu2IXjbVixbuw41atZKqoa0d3Nx5pctTZt7u80TgJtGkRWA+/HjB/bC0AeqQqVKPwXdwf36ImfOHPBcuIjfq3IzOQLuruAgWE+biq279kBdXR0jdAeiS7fuMJpg+oNThQbD7i5zEBZyGKs3bUERDQ1ZSSw3AFOIQwOCzevX4eyVawg/exbGBnrw8l2MFq1a/aDfsSNHGIBnu7mjU5euQt9fKEBhCCb6enj1MioJcGmGgTKmPnsaiYkmxnB0mfuDd5Yg+PbtWzh76hT8Fi7AwiXLUL9hQ5XqnWkBNzl4UBwIeYFMJ03mlL/rV6/meD6ajvvy9QtevXwFTU1N9mDQVKgweSnwNwDuwX37sGrZEngt8kPBVKa8BOCmv09RWBF5ZV+8eI7Y6BhMmjEDzVq0TKrw+tWrsLGYjikWlngaGSkAVwmpKSZ0945gTitORmE0rt7zoaP7YzZL+qC1bNQANrMc2fsoR5Mj4F67cgUmBnrsYNEoWhTL/BbDyNQsVcA9fPAAnO3tMHzMWI7Xl9usolwBd/+ePTAc880rHvXiBQI2bcTaLVt/ANyPHz9ioZcnAgMCsDkoCBpFi8mqG8tR39QAl2bTVi9bilevXuHB/Xs8I9G9V2+eyVQYOSV8vb3w+tUrxCfEY8jwEb+VmTW1G5XpAZdc60sW+fJiCEXMGI0oKOC/Q5cucLK1geNcV2zbvBn6RuNl6ZWQ1ROYAScjd8Cl/rRh3RrojTOCVo0aqSokAPf3Ow7FyTerWxvtO3WG+3wfjrUlo2fXYsok1K3fgF+md27fYjigNNX588tnQZ8c4ev7u0IhIOQd9/HzT9JXUYZCE2ggR1PnclqYk/wa5KgxzTBcDA9nb1dsbCy857li4vQZGDh4CLJkyZJ0+nfv3MGIQTocXz59pg0v3pGbyRHASCNyYIWFhuLdu0RcjojAxrVrsCloBypXqZJCQoJfnV490FdnIIxNzZA9WcyoHLSWo76pAa5CK8UM0OVLEVi7OSDVGQfSnAZ49P9Dx0+qVOZMCbgUcH7v7l1+gVCA8+QJJphhY4Paderi2dOn8JrniqlW1nhw7y78fRdCd9hwXuFOU0b58v03hkSld0JUlm4F5Ay41J+mmpli8gwL1K1fP+mD5eI4i+NGJ02bztctADd9t590I6+inqERw0HDGlrQHz8eo/QMMKRfX7Rq2wazXd2QkBDPDewODsaiBT7w8FmA+g0bpQCI9J2B6o6SI3zFREdjx/ZA9B2gw/o2rlUDYw0NU+g7z2s+v097durAnl1bp9mqE0XFNclR4+SXSPG4i+bPh9eixYiLewvdPn0wafp0Bq5u7dvyzgk0uMiVS56LneUIYMn1pRAPj7kuePbsKZxcXBEachiONjMx19OLBw6kv4O1FbwX+6OpDGPI5ajv94BLsbXkNCSvLcXsTzIxBnnGvRcthr21Fe9cRXpPMzfF+q2BePjgAQNu8eIl4L9qtUqf+EwJuKQgxdru3rEDaupqmOkwK2lK02jMKFjaOaBM2bIs9D9NGqNs+XKwsLFFzVq1VSq+qEw1CsgZcGkqzGvevKQLpS2qlq5egw1rVjPgDh89BiuXLsHq5cuTymj36MH9TU4m110UGFp37ODnmaxeg/rwXuTHC85MDQ3QuGlTXiCqsJCDB7B21SrWt2KlSnKSGHKFr9DDhzDHwR7x8Qk/1Xfvrp3wdJ0LjwW+P52lkIPYctT4yuVL3H8f3n+AgoUKYo67B3vJKbRmwjgD6Bka8iI/0pfugcLMpkzhnX3kZHIEMNJH0T+/9eEG/PzTFqD0Ppjv7s4/N2ralBfv0boc+lmOMeRy05dmHQb27p3UBRU8pV6gAGZMmoiY6Bjejk3xviV9Xzx/zj/HxsTAYNRIPrZho0awd54DOk6VlmkBV5UiiroyVgE5A27GKqO61uUMuKq7yoytSY7wlbGKqL51obHqNU1eo9wATNqr/fO1C32V01wArnJ6idIyVEAArvQ3RQCu9BoL+BIaS6+AtC0IABP6SquAcrULwFVOL1FahgoIwJX+pgjAlV5jAbhCY+kVkLYFAbhCX2kVUK52AbjK6SVKy1ABAbjS3xQBuNJrLABXaCy9AtK2IABX6CutAsrVLgBXOb1EaRkqIABX+psiAFd6jQXgCo2lV0DaFgTgCn2lVUC52gXgKqeXKC1DBQTgSn9TBOBKr7EAXKGx9ApI24IAXKGvtAooV3umB1xX59k4sGc3XDw8Ua/BtzRxtKXI9InmnJN6vNlETJw2DRfDz8Ng5Aj+u9/KVbxpPFmrRg2wfe9+TuUrLGMUkDPg0j6itNXPyWNHoVm6NEJPnflBpJvXr3N/uxxxEaXKlEHIydMZI+S/tCpnwD12JBTTJprjxbNn/6of7b/Ypkkj1KpTl5/3qlpastJZrm8eOOcAACAASURBVICbXN8mzZpjbcDWH3RbungR7y9KNnHadIwdZygrbRUnIzeNVy1fisU+Ppjr4YmW/7Th09y6aSO/D8j66OjA1dP7By3nOjlyxjPKZCYnveUMuFPNTRG4eTNraWhqChPzST+knCYe8POZz2XWbd3G2eXkZHLUl7ZknD7JHPj6FesCtnHKXnofHzl0KEk6eteu3LCJM/UltzZNGyPy8WN+F6f299/VPlMDLmUsadexE06fOI5ZLq689+2tGzd4T0JrBwfky5cfnVq3xIbA7fwSGjFmDK5eucIpfP9p0xZjhg3FjgMHf/ceiON/UwE5A+6pE8cR/ToaXbt3xxRTE6ipF4Cto1PSFdMm2bSxePNWrXgzfTsrS+TPnx+Tps9A1qxZf1MZ1R0uV8ClPStpr2HS98b16xg5aCCc3dwxZMS3/RUV9uHDe+iPGIGPnz7i+dOn8PFbguo1a6pOIBXUJDf4okuiVL2H9u9DmbLlULN2bWi3awOzKdNYb4U9jXyCE8eOoYt2N7x9+xZTzCbAYqYtl5ebyUnjUUN0cebkSU42Qskb2nboCEpfqjd8KD//ZcuVQ7f27eDt548evb7tNfr161ds27wJrrOdsG33XlDq3gWenljg75/kdMlIzeUIYKTHnp07MV5vDI6cPouI8HBOLBBy6gxrrLDtWwP4n/+0bcd/f/XyJfaEHMlIOX9oW276Pn/2DAN79wRl2atXvz6C96fkocTERDjazuT9cF3cPZBf7b+ZIycY6MPaYRaePnkCYwN9DB05EuNNzVSqd6YGXFLy3JkzmO/uxi8YEt/JzhblK1bE0P98IDu0bA7zadNx8fx5GJpMwGx7OzRt0QJPHj1CP52BXFZYxiogZ8BNrswCL0/Oyz3Xwyvp15SecM4sBxhOmIAqVash4sIFkHfGx98fBQvKJxWnXAE3ub4EWYP79YGb93z0H6SbolMeOrAfcx0dMWz0aCz3WywAN52PLDkFxpuao13HjqnWQFBAm7mPHKvHG+rLzeQEuJTNsHLVqrC1mJEEuJQ1jjzhigFY1dKaMDA2wRQLS5aS0vr6zvfGwX17sXztesTHx6NjqxZw9fJGzz59M1xuuQGYQhAF4JpOnsK/Ct62lb2NxUuU+EEzyrploq8HSsBx9Oz5DNc0+QnITV/KBLt21UqEHjqEd4kJPwDundu3ecCmP94YukOHpeq0uXPrFg8oOnbpyhk/VWmZHnApo9T9e/cwY6YN60q51hctW8EpEcka1ayONZsDeDqIRtfkva1YuTJo5BIbE43e/Qag38CBqrwnoi4lFfgbAPfNmzfQ7dMb1vYOaNG6ddIV0rS59bQpsHVyRrny5Tlt4VSzCfyBo6xncjE5A+7R0FBODUmDh6pa1THH3R2FChVOko4zE02ZxKl5SVNvt3kCcJXoWPQBIn2fRkaiZKlSsLazR778+VOtgdKg0zvVeZ471NTVlWjlzxSVE+DSFR8/ehQGI4cnAS6lhif9FIBL358e/w+udv9Jf0we3FXLlsLHwx07DhzCxw8f0L5lc7jN9xGA+y9dKDr6NTauXcuDCcoKR57C8WbmyJEjxw9H3bh2jYGrR+8+MJsy9c90zDS2IjfApdP+PlVv8ktZ5DMfm9atY4cNZedLzXYFB8Ny6mQsW7MWDRo1TqMSaSuW6QHXYvIk1K1fH7rDhnOOZJoSOnf1GrJly4ZLFy9g+KCBOH/1OhISEvD+/TuOjaIc1a9evUL7jp05heXWXbvTprYoJYkCfwPgujg68Aff0MQ0xShWAO7vdwnKLx8X9xaXLl7EKN1B/OGaZmWdVHFYaAhDrZfvYpw5dVIArpKSk9eQ9P38+TNMxxmgfafOP42xbVSrBlas24Badeoo2cqfKf63Ay6pRAOOCYYGuHntGr7+x6tLM5DCg/vzPkQeRrPxhhgxZizHiK5ZvhzHwy+gVOkyKQ6iEJsZk8w51feSVWtQrHjxP9Mx09jK3wa4TerUQsPGTbDAzx9Zs2X74SqfPX2Kbu3bonvv3pxSnRyIqrRMD7iD+vTivMi0wIy8sp3btMaZS1f4ZU6jvSrVqkHfaDznTabRdfOWrdjLRla/USPYWkzHxsAgVd4TUZeSCsgZcD99/IgNa9fwR2myxbf4WjLKx02xd1mzZoGdlRXGGBiwh3HPzh3Yv2cPe2TkZHL14BJ8xUS/RuEiGvzM1q9WBc1b/wNXTy9ERb3gOPoL589jtp0ty0me9FevXrJ3hsqoOvf579wzucEXXcuXL58RGxPL/TZHzpxYt3oVzp0+zf3zwf37rF+hQoXYOTB84AA4OLug5T///I4Mkh4rN42/9+Du27Ob+6qX7yJUqlwF1SuUg4PzHA6He/bsKUqVKp0ijjHiQjgmGBiwh6x23W+zjhlpcgQw0oPWNlDs8sWbt3Hl0iX20FLYR+u27fi7r6mpiZy5cvFMxfrVq7h/y22BGV2HHPX9mQd384Z1sJw8BcvXrUerNt8WUNJ7gkJASO+4+HgeMOfMlROzXOZCU7OUyrtupgRcCnw+cvgQj9IoXmzCxEnoP3AQx9MO7teXPbrksX0Z9QILlyxjGKEA9Fq16/BioKCtAQg9fJhf/to9eqKzdjeV3xhRYdoVkDPg0geMFpd169kLJUqWRL58+dBngA4o/o4e7CkzLLHc3w/37tzheLzjYWEYpa/PCx3kZHIF3Li3b3nKljxZiQkJ/O857h6oVr06enbqiLYdOvAzrDB6jkWIQtp7Fr0HVy1fhjcxMShcpEiK/tmzc0d+b/bu1x/GBnq8Ir1l629w+0+79qharVraG/pDJeUEuDTwvXThAg8aBg4eggG6uhyHb2KgD42iGjyLSGEhc9w9ceLoUUybaIbFK1ZCS6s6Qg8fYlA4EnIYrdu0Zc8k6Z/RJkcAI022btqESROMOUTs4f37uHnjOhxdXDnO1mrqFA4R+fT5M4YN6M/f83/afXv/dtbWRtly5TNa1qT25aYvebzpnUthCPHxcTCbPIUXS9JuCbQegt7JATt3Jzl2jMaMxuPHjzgEx9N1Li8QHqWnn7TYT8/QSKVaZ0rApSnN8HPn8OL5MxaTtloh71lJTU0GjUsRF/n39LIuoqEBCqR+/vwZj6gpZocWBtHx5H2jwGhhGauAnAE3eX8ilXgHjnbt2aNLuyRo1ajB/Yv6E00DU39TQELGqpqydbkCLp3lo4cPWD8yhX7kVTgedoRjbunZVhh5EG7fvIl6DRtCXWYxonKCL4VeFPNJC0WuXr6UQl/64VjYEZ7iJfC9cO4cYmKik3Su37Ah77wgN5OTxgf27mFHisIIbul9kFzvOvXqo3yFCuyMoZC5Bo0b4+uXrwg/d5YXnCneJ3KAW7oOuQGYQlv65pNTi5xbZDQzW02rOmiK/HJEBKi/0gJJAt/k1qR5c5QoUVI23Vhu+lL/pX6ssBw5cqJBo0Yc50x6E+gmf/+eP3sWiYkJqN+gIY4fDUvR/6mOXn37qVTrTAm4KlVQVJbhCsgZcDNcHBWdgJwBV0WXmOHVyAm+MlwMiU5AaCyRsP+pVm4AJu3V/vnahb7KaS4AVzm9RGkZKiAAV/qbIgBXeo0FfAmNpVdA2hYEgAl9pVVAudoF4CqnlygtQwUE4Ep/UwTgSq+xAFyhsfQKSNuCAFyhr7QKKFe7AFzl9BKlZaiAAFzpb4oAXOk1FoArNJZeAWlbEIAr9JVWAeVqF4CrnF6itAwVEIAr/U0RgCu9xgJwhcbSKyBtCwJwhb7SKqBc7QJwldNLlJahAgJwpb8pAnCl11gArtBYegWkbUEArtBXWgWUqz3TA+7Z06fw4N59tG7blrOWvH/3DpS3nvYfJMuvpsZ7FNLWYPv3fMtY1qmrdlIaVdrLsE+//sit4gwcyt3GzF1azoBL29Ls2bGD97itWbs2aNulK5cioF6gIG//Q0b7LIeFhPAG+bRXrhxN7oBL6Xh3BgXh69cvKZ5PhZa0zRLtHfrh/XvWnTZ4Ty1NZ0ZqL1fAffL4MffPhIT4pPfh9zrR1msnjh3lvVnlqi+ds1w1vhxxEefOnEH/Qbq8Zyj1Z+qvybOTnT9zBjdv3pD190ZugEtbqZ0+eQLPnz5D1x49UmTKIj0vhJ/nvYfp+/+9vYyKQtC2rfzrChUr8fs5Z86cGfmKkOU2bLQXbljIYdaF9ntX2Kb160D7lBcoUDCJr74X797duzh8YD//uk69emjUpKlK9c3UgDvN3AwFChZE+NmzmO3mhqrVtECdmpI/0H6DtE9m3rz5eLPneXOckSN7dgZdSvbQvVdv0PEdOnfmjY3lsg+hSnvHX1KZnAH32dNI9O7SGc1atoKjy1zOluM734v3VFZ8vIIDAznl81gjI4zRN5Cl6nIH3BX+flizcgVnGVy/dRunh1TYk8ePODucmpoaws+fA6XtpI3GKaGLnEyO8EX7CW9Ys5oH8Hdu3cSaFSuwcsNGtGjVOoW+NLgoVLgwLoafl62+cgZcZwd7rF2xHJZ29hgyYiTu3L4F2hR/35GjSTpTYg0aINs5zVY5CKjqOZAb4DrZ2XIGM+q/23btRtFi31LvPn/2FKMG6yImJgYNGzfm90Fyu3vnNuytrFCxciXUrd8ApUqX5mynGT0olpu+NBBzmGmF4G2BqKpVDcH7D7KMyxYvxtpVK6FnZISAjRsZcA1NJqTgJBpcONnaoHmr1qhYqRLzV41atVTVFbmeTA24tLEz/WdjMR3ei/zYg0ueHjtLC3j6LuIPIhmV8XJzhdEEM868QRl6Ii5c4A2MCXCFZawCcgZcSixgamjA6U6dXOcxVCUHXPIoEpiRd2zvzp1JL4iMVfTH1uUMuI8fPeKUj+07d+YsZd8DLnlxPnz4wN6be3fvoH2L5py5iNL1ysnkCLhfvnzhzfFz587N78ZWDevDyt6e34UK+1v0lTPgUipZgtddQduxNzQM0dGvUwDu/Xt3OXV8r379cePqVQZhOZrcAKxGhXJo17ETD7ySA66/70JOTvLwwX2Uq1DhB8D1W7gASxf54siZc7JyXslNX3onGI0ZhU+fPiNHjuz8/SJeolTIlatWg80sR/h4uLMnfHNQMDSKFkvqthNNxnNf3r53v2QDh0wNuKT0ti2befrN3WcBC39o/z5YTZvK/ybv7pbgnTxdROlUKYWfg7UV2nXsyFMVHTp3QdHixaChUVSO75pMc05yB1zraVPQpHkL7N+9C8vWree+pPDg0svA3WUORukbYOywoXBydeXUm3IzuQIuAdjmDetx9tQpNG3RApZTJv8AuMm13L1jB+h+kMeGZmLkZHIEXNKH3n+U8WlbwBYEbNjAueUp3Ca5UVrz6NfRfC9oStht/gJUqlxZTvLyuchVYwLccuXLgwZrNJig9McECQoPLr0z3r17x7M+MyaZY66nNzRLlZKdvnIDMBp8+c73xsa1a5IAlzSePMEYUy2tYW9lkSrgkvZbNmxAhUqVeJq9W69esHV04hndjDS56Uta0CyPib4eXr2MYsB9+TIKJvr67JUlp87alSuwyGd+igEGHVdfqyqioqJQpmxZvHzxAjNsbDF2nKFK5c30gEv5kNXU1VMVtmu7NjAYb4x+OgP5ATlz6hR7MypUrIgH9+8hMfEd8uXLCy/fxSq9KaIy5RT4GwDX1skZM2dMQ7sOHREbG5MEuJRjnnLRz/Oezzm9Tx47hqVr1ionwB8oLVfAjY6OxlTTCejcrRvHLpqPN/op4F6/dg2TTcaD0p+SB0wxQ/MH5EtTE3KFLxo80FoDCt96//4dJk+3QKOmKWPldm7fjiMhh/HixQt8/fIZVvazUKVq1TRd958sJFeNFYBLMYwzp09DnwEDQN8mAlyKcaQ+bjxxEsqVKwcHm5nQ7t6dHSxyM7kB2PeAW7iIBig2NPTQQbi4e2KYTv+fAi55eI+eC8eenTthMXkidhw4yKmpM9Lkpm9qgEtpkec5z8bu4CB23JADkUJuknvQFYBLqanXbw2Ei+MsrFy6BFfvPVCpvJkecMeNHokhw0egTfsOPwg7qE8vGE4wZSghC9yyBVFRL3iqk6Y823fqjAnj9BG874BKb4qoTDkF/hbAJW8j9almLVqiU9eu7I2hODuKC61Zuw4oXvfBvXs4eOwEipcooZwIEpeWK+BeDA+HTq8eqFW7Dt5/eM/x9LrDhmHyDEuOm1PY82fPYDR2NE8D04C0bLlyEiumfPVyhS/FldC0ebO6ddCxSxf20JKn8Xu7e+cO+nTtjDEG42BsPlGyqUfl1f12hFw1VgDusFGjsXTxIg6Bu3opAiGnzuDMqZOYPMGEPV05cuTE5YgIDBs1Spb6yg3AvgfcPHnz8SwPaapVvQaOHw1jr6yzmzu/k7Nly8b9hDy4tAjtePhFhBw8ABMDfew6FJLh7w256Zsa4NLvKMb57OnTeJf4jhfnv3r1Cv4rV6FgoUJJjy55cKtqaWFjYBAWeHlgtr09nryOSe+jnepxmR5w61atjC07drG3gbwUZLpDh2F7QADWr1mFNZu2IHuOHPzz27dvoDN4CLZu2sTlvuIrbt24wVMXwjJOgb8FcGkKkrwyCzw94b5gARo2aYou/7TCsrXrUL5CRRZwvN4YDB42Av0GDsw4QVNpWa6AS6v2Y6Kj+Yxp9xPrqVPhv3o1Spcpi9FDdNGy9T+YOcuRF4Teu3MbGwKDePGoHE2O8EXTjutXr8Zog3GIjY1Fwxpa0Dc0wmgDA4wYNJD1HTxsOO7fuwftHj3w/PlzNKpZHW7zfTB05ChkyZJFVlLLUWMSSAG4o/UNcPvWTUw0Ho/HDx/izOWroHhRWihpaGLK8aDHwo7wokmnua4pgEEOQssNwL4HXIoBffvmDcjLSDZ84AB+V3gv9oP/wgXYuG4tfJctx6ULF9iTTjG4O7YHYldQEFZu2ADyAGekyU3fnwGuQiN6NxuMGonuvXphxJixmD7RnHeoogEF6b19awCHNVDo5+fPn/lbqErLlID7+vUrzJo5k7e1IaMR3MxZs9hTS16e8HPnOH5s/mJ/FC5ShEfMNNKj1a00DUoxZnR8tuzZELh7ryrvh6grHQrIGXBpCzDPeXNhYj6JY+bo5/Fjx8B44kRkz56dt0ixmfXfARLFgB8LC8NMh1npUEK6Q+QKuMmvOCw0BLRq2s3bh8OO6Flu2rw5+ukMwv+1d55xVR3dHv7bUIMVxSRWsKQo9gqKKKjYULFGo8aGDRWVJk2qdEQBG6KisfdeETuiIti7iT2GqGisYPC9dy1zzgXj+7scPRuGMPMlAefMPvuZYe9nrz0zy3e6O27fuqWuTtOOJk61z7ZtkHL0ctayqPK1Y+sW+E734JNo3LQp5i1awrtVqPjS+I2aFY5VPy/jmxTtMCPa+FX1gKiMiR9dH2hcUqGfD8bF4ed163kXC5rz3KKVMf+b6v7l5OaOrytXztngyqVaoglYq0YNsp25s7sHrPv2U/+OxnDlKlV5vC6YE8Vrcuj6QbxVLqCvX4n9QMU/l1B+9DCi8SVZte7aWf1d6brr7R+A/Xv3gq4bVLJeD+hBjqK7Hj5+PN57dbHk+f1ZfUubfAuk4GoToGwr7wmILLh5T0c73yA/CK52zjTvWhFVvvKOiPaPLBlrn2nWFkUTMGXPNvdbl3w1Yy4FVzNesraABKTgKt8pUnCVZyzlSzJWnoCyR5ACJvkqS0Cz1qXgasZL1haQgBRc5TtFCq7yjKXgSsbKE1D2CFJwJV9lCWjWuhRczXjJ2gISkIKrfKdIwVWesRRcyVh5AsoeQQqu5KssAc1al4KrGS9ZW0ACUnCV7xQpuMozloIrGStPQNkjSMGVfJUloFnrUnA14yVrC0hACq7ynSIFV3nGUnAlY+UJKHsEKbiSr7IENGu9QAvuhXNn0b9nDybmHxLG2WOo0MbEro4OePniBe89OMneHufOpGD8yJH873MXLeJsSFTaG7fChu07eDsxWfKGgMiCS6l4RwwexKk3aR/Ad5mZWLp4EQwMDdGxcxcGRskKXB3t4e0fiGYtWuQNxP/nqCILLm3h5+rgwNngiB8xDwsMgJ2DozphxtaNG+Hr6YGte/YJt7WSCr2ogqvim/r7Q06ese/IsY+Olp9+6M/ZHnVLlYJ/SKh6fIs0oEVlvCQmGpFhYdix/wCPT9pX2GXqFKzatFmNLyIsjLexEvl+I5rgvn71CiH+M3A66RQWL1+JChXf72Orup/TlmvNW7bEjJAwVK2WPUuZajxX+vIr+IeGwqSNaZ4PZdH4ZqSnY27kbETPmcNs5sQs4u1Wnzx+jD7du/GWYJTumPyqYeP3zpS11DV8n3CnzrffZusfbYEusIKb9uQJZgYHwjcwmPdrW7NiBWbPm88ZN/w8PXhfPF3dUujYtg3WbtmK+ZERGDJ8BK5cuoQSJUqifYcOGNS3N/YcPKytvpDtfCIBkQX3wf376NO9KwvtrLnzUK68HuZFzlan6qXMWrR/KOXrbv6/+1x6zfD/RArKfkxkwd22eROC/XxR59vvEL10Gehv28vNBW5ePrzXIu3NOnXCeL7otjA2wcQpU5WF9Ymtiyhfz54+xbrVq0ApZK9evoxhAwcgICwcg4YOVZ8lJdugTE8vXzzH8nUbPvHsc+djIjKmM6f9QSljlnHrNvALDsGtX3/hLIeUqpfK27cZMG3eDE2aNUPnblboYW2dO8A0PIpoAmZpZoprV6/yg5kqVSzJ7ZQJtnB2c0enLl0/eoaR4WGc3bR69Rqw+WkoqlavBr+gEOjq6mpIRLvVReN79PAhzr5JSV2MGzfE61evcfrSZczwnA6b8eM5817/nlZoZ2EBJzePbNkPxw4fBi//APz24D5fPyiL37iJk7QKrMAKrooipU/dvGE9Eo4c4YxktMF2tRo1MPinYVzForUxpjg540xyMsZOmIhAXx+0MDbG3du3Yd2vP2rWqqXVDpGNaU5AdMF1tJuEosWKok1bM47iZhVceksQs2A+b3Qd7OeHjbt2oWJFfc0hKPwJ0QWX8p2fSUnGxCn2aGVikk1wf715E8uXxnJqZLtxYzi1dpmyZRUmpnnzosqX6kxOHE/AgJ49EBIRiX4/DFSfIIkvpTat37ARGjVpwmwpw5l+pUqaQ1D4E6IyJsGlNKa7t2+Hd0AgKupXzCa4iQnHsH7NavTpPwBrVixHYFg4SpQsqTAtzZsXTcDcnBw5XXTcnt0suBUq6jO/0MAAjLAZzQlhqhsY8Hileh+WFy9ewMV+KigjWsis2ShVurTmULT4CdH4Zj01ininnE5GQsoZTohFhYIKQ/r3g2m7dpjq7AwdneL/oEGJtOj6MWTESIwcPUaLtIACL7gUofDxcEM78w7o2qMHzFo0w5yYxepwenOjuli6Zi2WxsSA8tkXLlwYtb+pg9TfU3kKQ/devfj1syx5R0B0wXV3csBwmzFwd3bkCOOu7dvUEVx6evXz9OSHq+ku01jOho2yyTuY/+XIogvu6VOnOB2ko50dohYuxLyI2eoILqXapJTa4ybZYcSPg0DpUCnvvGhFVPmiKQqxMTH45eYNGBrWRFD4rGxTspJOnsAEGxuYd+yIukZG2LR+PbpaWfHD3MekIS+5i8pYlaq3StVq2LZ5I0aMGQvnyXbqCK63uxtHb1sa08ObK7+F+L5evbxE+dFjiyZgH6bqLa9XAfMiIzhNLAWuMjIy+O1ZVHQMGjRq9I9zoixbPS07YbStLX4aOYqzT+ZlEY2visWvv9xEPysrvq5SGl76OSo8nDN3kjdR6u76DRtmQ0dvKfy9vZH68CG+KKWLkFkRHGnXZinwgkthchNTU86n/ujRI3Rpb4aki5d5INOTxeB+fZF8+Qrnr379+jXnp27eqiUeP3oMs/bmCAsKwIbtO7XZJ7ItDQnkB8H1nBEAepV+7cpl1KxdWy24K5ctxeWLF+ETGMQ5z/29vXA85ayGBJSvnh8E18nVDSEBM6BTvDju3bnDglu+fHmEBQXCqEED9OrTl29uJLszo97PGROpiCpfr1+/wrOnz0BrFiivvK3dZNhPc1GjUwluaGQUp/Kla2SRokU5ZecXX3whEmKIylgluJSq19/HG3WN6mFFbCwL7r27d+Hp4gwv/0DoVdCDp4sLp6DuN3CQUGzpy4gmYP9NcGmdTezK1Xjz5g2sOlrAJyAI3Xr2/AdPc5NWKFuuHAuwtuXrUzpPNL50DrTmwWmyHeg6cPzMOf6bpyk1aU/SOK20y9SpqFHTEH6Bwdki4DS1iT5L1+MZXtPRsHETfnjWZimwgktPFvS6kubZ0NQDKvS01rldW5y6cBGZme/g5eoCg5o1+d9JcOdHRaJV69a4d+cu12/aojncHR2xdus2bfaJbEtDAvlFcGsYGKDJ99/CsFZtDBs1Cl26W6F7B3N+wi2mo8Nn/TYjA8vXb0A9o/oaUlC2en4R3LS0NAzu1wc6OjpYsnI1aI7zj3174/mfz1GkaBFk/pXJCxpIcGl+rkhFRPmi+cvPnj1FuXLlQdO5Gn1bh+eJ0oI+Yk03M5pnTq8YJ9k7cOR22tQpKFuuPNy9fVBSsNfoIjKmMagSXHq7sHn9esTGLERq6u84djoFe3ft4ik3JGuFChUCLZzqM2AAnN2nC8dXNAH7UHD19CpgUfQC5rtp5268evkSA3r1gG9QMJq3bIU/nz3DV5Ur82JgHw930BzT+UtiYVS/gRCXChH5LoiKRGT4TBw4noivK1fh6wS9GaepSiSxAT7eOHLwANZu2cb/Rn1C05f+SE3la/CzZ88wwWYUrl+9gsSz57XKuUAKLk9qtrGBXsUKMG3Xnl+jtW5jynNxaFeFlibGePXyFe7cvo2FS5dxR2zZuAHf162H1m3bYsuGDTh29DDeZb6DecdOfFGXJe8I5CfB3b1zB+zGjmFBMDCsicnjx2L1pi3q+Yo0jUFfvxLvACBSyS+CS3OdI2fOS5GEWgAADn9JREFUxJKF0Rz9Onf2DHZt28YLd0qXLo2nT9Pg6TINPaz7wKJTJ5EQCxldpAf7ZUsW8dw5EquFc+fCPzQMdesbwapjB148EhQ+m1eq01xnCgDQol2Knrc2zftV5x92cH4Q3MePH8Fh0kScOX2ab/i0wFm3lC5PXSpatBjOpiRjdmgoAmeGo9KXXwo1hkUTMBLZQ/HxOHUikaco0St0eugloeresxd+e/AAz58/54cxumZQ/VUbNyHl9Gl4u7li0NCfUK/Be7ml6LpqbmleQReN74mEBPTv1QM9elmjubExuxTtlpB86hTS09N5gS/NfzYxbYuxthMwxXY87t27yxHx2IXRMKxdG08ePUJ83D707N0XI8fIObifPbYoYkbb2bx5/YrbKlqsGG8VQvOfbly/xhcWKmYWHaCvrw+64Dx88Bu++e477kDV5wsXLsSri2XJWwIiCy5JAW0DVr9RQ96Vg34+GB+PBo0aolDhwrh/9y5HDlSFXkfSRZfGo0hFZMG9f+8u735St54RTy2in8+dOYt25uZ4+PA3vM14y3+7VOiCS1NCaLEI7WwhUhFVvmjLqqQTiYyqYqVKaGduwVJwKH4/b8NG4/fhbw9w4vhxfgNRpVo1/l1ez1f8WN+Kyvj82TP4QrcULzalQj/fu3uPhYxe4dI2lMSaCr1WTzpxAo2bNcvzVf0fMhZNwNavXpXtKzZp1pyniNH9//avv/C9v3HTZqC3axfPn8cvN25wEOvmjRv871lLF6seec5bNL5ZfUnlUsSTggnHDh9GevoblNfTQ7OWrVC2bFmcTDyOV69e8f0tIz0D+/fuYcT6X34J49atP7oI7XOu0QUygvs5wORnxSMgsuCKR+vTvpHIgvtpZyTep0SVL/FIffo3kow/nV1OPimagOXkO+enOpKvZr0lBVczXrK2gASk4CrfKVJwlWcs5UsyVp6AskeQAib5KktAs9al4GrGS9YWkIAUXOU7RQqu8oyl4ErGyhNQ9ghScCVfZQlo1roUXM14ydoCEpCCq3ynSMFVnrEUXMlYeQLKHkEKruSrLAHNWpeCqxkvWVtAAlJwle8UKbjKM5aCKxkrT0DZI0jBlXyVJaBZ61JwNeMlawtIQAqu8p0iBVd5xlJwJWPlCSh7BCm4kq+yBDRrvUALLmXR2LV9OxMzadOGtw+hvdsorz0lfaBC+9716tsXj/74Awf3x/Hv2ll0QEV9ff7/jevW8lZhJUqU0Iy8rK01AiIL7pvXrxG3dw9q1qqN7+rW5T0Yr1y6iNJlyqJ6jRrMgMZWwtGjnKZXtH0tVZ0ksuDStmrHjx5FGzMz5vfmzWukJCWhYZOm6kxav9y8iVOJiZxaW1dXV2tjT5sNiSq4/xa+1FeiMr588QLOpKSgh3VvHp9//vknEo4cRudu3dVDjLYbvHnjutD3G5EFl1JO031ddb+m+39y0il07NxFzfjYkSPI/OsvGLdpI1yaafqSovGlpA3E8NqVq3+7kQWqVqvGW9nt3LaV8wlQwgfyK5UzZb1mLo+NVf9InqXtfYYLrODSPo4L5kSienUDpJxOYvHw8PHldLy+091Rv2EjlClTli82lMIvPDgIme/e4dEfqWjbrj3/kbg7OaKliQk6de6C4lJwtXmv16gtkQX3fS7zjjBuY8rZcijD1rzI2epUvXSi27dsQYC3J2xsJ2DYyFEanXtuVRZZcHfv2A4X+6kYPHwE7J2ncWIWyvxEyQZU2cooK9HeXTvh7uOLzl275RY2jY4jqnz9W/iKLLiBvj74ecliePj64YcfB7PIjhsxnJOVqEqvzpZ4+9dbTivbtHlzjcZWblUWTcCynvcP1j1BD7ohsyNg1t6c7/vTXaZh2973gSsqLRvWR6MmTeHq6cV744pWROObknwae3fuhGHNWqAkRW3ammHxipWInjuH73UkwEuiF2Dk2HEYMnxEtoeGpYtiOHX6+EmTsWzxIpiZm7ODabMUWMFVpZOjTYgpi8baFSsQEDYTL1684LSJs+bMRekyZZg1JXqYHRqCsRMmccS2zjff4tKF86hrVB+WXbtqsz9kW59AQGTBpTSmE8fYcKrnGSFhaNCoUTbBzchIBz3Fvnj+HHF79mDr3n2fQED5j4gsuNs2b+LsWUcOHkLc0WOcYCCr4Kr+finXOf2dr9myVXlgn3AEUQX338JXZMGlew4lISFZ2HXwENKePM4muLdv/QoPZydYWffGjWvX4DLd8xNGmPIfEU3Asp6xVacOHLh68vgxwiKjcO3K5WyCe+H8OQR4e6Nxs6aoZ9QAXbr/X/RceXI5O4JofClS+9fbt5w4Z9SQwThxPAGHTiahEIAyZcrgxcuXfP/76quv4eUfoH6jRmdr3cUSf2VmYuuefbC1GYW7t29h2779OQORw1oFVnBVfDLS0xERPpND/xOmTMXhAwfgPHUy/3OlSpWwYccupD15Anra6GbVA25OjjDv2JEjtiS3FSpWRPnyejnELaspQUB0wXV3cuBMLpS1ZcnKVVgcvUAdwaXXZDODgzhyO/zHgQgKn4XWpm2VwPRZbYouuKdPneLsORfPn4NfcChmeE1XR3Bp+sLhgwcw3m4y2rdqiWVr1qKukdFn8VDiwyIL7r+Br+iCSxHD27du8Ti2srbmdLKqCC7df16+fMlTGJynTEZoRAS+rlxFiWH4WW2KJmAfCu7gYcOReOwY37tpOpOnq4s6guvm6IAGjRujSOEiuHTxAhxd3VCyZMnP4qHtD4vG911mJlJTU0GBnB/79kb/gYPgHRDIUz0p4+vDBw8wauhg+AQGoVefvtlwzIuIQHhIEE9doAAPRdYttfx2rcALLkUnTh4/jpFjxsKgZs1sHWBpZoqxEyfBum8/rFgay08nFPmtYWAISl9JnaKnp4fwufO0PY5lexoQyA+C6zkjAK4O9ujUtQs/MNWqXQdWvayRmJCA5bFLEBoRyQ9RSSdPYuHSZRqcfe5UzQ+C6+TqhoG9rTFkxAgciNvHgks3sZj581C8eAkMHTEC/t5enDJykr1D7oDT4CiiC25+55sfBLdLdyuO1PYeMADhQYEsuPRW0WHSBNjaTUF1AwP4Tffg6KJ5x04ajK7cqSqagH0ouLaTp6AQCuHwgXhYduuGEP8ZLLiPHv2B7hbm2HXgEO7fu4eIsFD4BYcItyZCNL700EUBm+tXr2Df7t2YERyKDp07c5Q8ek4Uv/1+/OgxRo4Zgw6dLFFMR0fdJRR4WDA3Cs/SnuLJk8ewc3BE7379tTpQC7Tg0rxaWkAx3s4OBobZ5ZYo05yd0eNt1RcSkmF6UvlCVxcU+bXoZMnh96xzeLTaO7KxHBHIL4JLr3J+7NcHrYxNYGFpyYJrazMSZ5KT0bBxYzy4dx+U2zs+IVG4C2t+EdykUycxKyQYOsV0MHPOXI7AjB42FOlv0lG1ejVcv3qV5+VGRceopyDlaJDlQqX8ILj5mW9+EFyKMNID2cXz53Hh7FkcPHESSSdPwGHiRBjWqoViOsVwNjkZg4b+xG8kihUrlgsjM+eHEE3APia4xiat4ebkgMpVquL4saN8/167cgVPTWxnYYGXL15yMGvhsp9hatYu5yefCzVF5uvj7oafY5fg57Xr0MqkNdMgAaa1SlevXObfV6hQkX9Pa6BoTrlhrZrwmhGAyJlh2Ll9G85fv6lVigVWcD2mOUNfXx/DRtnwKj8q61av4v/2+2EgSGYpartszTqeLE0/P01LQ98fBmLz+vVcr1DhQrhy8SLPLZEl7wjkF8GlV5Chgf5YOGcOQiOj0KxlS1i2NcW8xUv4rQAVu3FjQDc5emsgUskvgksLQV0dpuJAXBxHv+7fu4sgP19M9/WDXoWKoCkh4cGBmOzghEZNm4qEWNgV/nTtoykKFMHNz3zzg+AOtxmNa1evwn6iLe7duYNTFy6x8N65dQujxo2Djk5xJB47ioPx8fALCka58uWFGsMiCxjNwaUILi0yPXQgHhNHj0YNQwOs3rQFU2zHwaSNKTpYdmaeyxbH4Pmfz3ldjkhFNL7bt25B2bLlYGpmxgx379iBFRs24kRCAk9XIHeynzQRtJtQZPRCvhY//O0B7OwdMbhfH7Tv0AER86Ph6+HO65tSrlzTKu4CKbiJCcfg5eqK1NTfGSbtlODtH8CRWpovkpyUhNp16rB40BPH+bNncPTwYQwZPhylSpWG6vNFihbBjrh4rXaIbExzAiILburvvyMs0B+T7B1RpWpV0M82Q4fAzsEBRYsWQ9ze3bwqWlXi9uzG0UOHhHtoEllw4/ftxflzZzF6/ASO2NLPs0NDOQJz7MhhnkpEK3ipZGRk8ApfetigCLpIRdQI7r+Fr8iCS4uY6fpAARQq9HP8vn1YvXkLB1qMGjRQR8Xo9S/NHaWFZqpdQkQZx6IJWFYudN2l60Db9u351/QzFQpQLY9djFHjxqsjjHdu38KoIUOw9/ARUdDy9xCN77OnT3lO+MkTifz9KEpbz6g+X48njxuHtLQnqFvPiBmTU9H0G9pZiH6+ef06JtuOU/Pdvm+/1sdzgRRcoUas/DKfTUBkwf3skxOkAZEFVxBEn/01RBXczz4xgRqQjJXtDNEETNmzzf3WJV/NmEvB1YyXrC0gASm4yneKFFzlGUv5koyVJ6DsEaSASb7KEtCsdSm4mvGStQUkIAVX+U6Rgqs8Yym4krHyBJQ9ghRcyVdZApq1LozgflO+NP6D/2j27WVtSYAW+/G20pDjR8HRUKhQIc72J4tyBEgO3knGygH+ew6jZKwoYshrheSrLIGcty6M4FYtXRLpme9y/s1lTUngbwIygqv8UJARXOUZywiuZKw8AWWPICO4kq+yBDRrXQquZrxkbQEJSMFVvlOk4CrPWAquZKw8AWWPIAVX8lWWgGatS8HVjJesLSABKbjKd4oUXOUZS8GVjJUnoOwRpOBKvsoS0Kz1/wGRpiWRvI+zeAAAAABJRU5ErkJggg==\"\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthical Approval: Not applicable.\u003c/p\u003e\n\u003cp\u003eCompeting interests: Not applicable.\u003c/p\u003e\n\u003cp\u003eData availability statement: in Supplementary Information there are all the references linked to dataset.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRole of the funding source\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement section\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors wish to thank Edoardo Mannucci and Benedetta Ragghianti for their external support in collecting data and revising the final draft of the present manuscript\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eDeclaration of Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBarbara McGowan has received speaker and/or advisory fees from Novo Nordisk, Eli-Lilly, Astra Zeneca, Janssen, Pfizer, MSD and a research grant from Novo Nordisk. BM is a shareholder of Reset Health. Andreea Ciudin has received speaking fees from Astra Zeneca, Boehringer-Ingelheim, Eli-Lilly, Novo Nordisk, Sanofi, Menarini and research grants from Eli Lilly, NovoNordisk and Menarini. Member of the DMC of Boehringer Ingelheim. Jennifer L. Baker has received a consulting fee and is an advisory board member for Novo Nordisk A/S with fees paid to her institution. Luca Busetto (LB) has received payment of honoraria from Eli Lilly, Novo Nordisk, Boehringer Ingelheim, Pfizer, Bruno Farmaceutici, Regeneron, Rythm Pharmaceuticals and Pronokal as speaker and/or member of advisory boards. Dror Dicker has received speaker and advisory board fees from Boehringer-Ingelheim, Eli-Lilly, Novo Nordisk, Astra Zeneca and research grants from Eli Lilly, NovoNordisk and Boehringer Ingelheim. Gema Fr\u0026uuml;hbeck has received payment of honoraria from Eli Lilly, Novo Nordisk, Regeneron and Astra Zeneca as speaker and/or member of advisory boards, and payment of honoraria as member of the OPEN Spain Initiative.\u003c/p\u003e\n\u003cp\u003eGijs Goossens has no conflicts of interest to declare. \u0026nbsp;Borja Martinez-Tellez has received grants from the EASO New Clinical Investigator Award 2024 and the EFSD Rising Star 2024, both supported by the Novo Nordisk Foundation. Matteo Monami has received speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Bristol Myers Squibb. Paolo Sbraccia received payment of honoraria and consulting fees from Boehringer Ingelheim, Chiesi, Novo Nordisk, Eli Lilly, Pfizer, and Roche as a member of advisory boards.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eEuan Woodward \u0026nbsp;has no conflicts of interest to declare. \u0026nbsp;Volkan Yumuk \u0026nbsp; \u0026nbsp; was engaged in advisory boards and lectures with: Novo Nordisk, Eli Lilly, Rhythm, Regeneron.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the authors approved the final version of this manuscript. Dr. BM is the person who takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eAuthors involvement in each of the following points:\u003c/p\u003e\n\u003cp\u003e1. Design: BMG, AC, LB, MM, DD, GF, GHG, PS, VY\u003c/p\u003e\n\u003cp\u003e2. Data collection: MM, BMT\u003c/p\u003e\n\u003cp\u003e3. Analysis: MM\u003c/p\u003e\n\u003cp\u003e4. Writing the manuscript: BM, AC, MM, DD, BMT, GHG, PS\u003c/p\u003e\n\u003cp\u003e5. Review of final draft: \u0026nbsp;all the authors\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGlobal Burden of Disease Study 2021. Global, regional, and national prevalence of adult overweight and obesity, 1990\u0026ndash;2021, with forecasts to 2050: a forecasting study for the Global Burden of Disease Study 2021. \u003cem\u003eLancet\u003c/em\u003e \u003cstrong\u003e405\u003c/strong\u003e, 813\u0026ndash;838 (2025).\u003c/li\u003e\n\u003cli\u003eNagi, M. 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Regulatory challenges for new drugs to treat obesity and comorbid metabolic disorders. \u003cem\u003eBr J Clin Pharmacol\u003c/em\u003e \u003cstrong\u003e68\u003c/strong\u003e, 861\u0026ndash;874 (2009).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 1 and 2","content":"\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"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":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Obesity Management Medications, Network Meta-Analysis, Obesity, Overweight, Efficacy, Safety","lastPublishedDoi":"10.21203/rs.3.rs-6449183/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6449183/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: There are different types of obesity management medications (OMMs) are available but their effectiveness in reducing body weight and preventing or reversing obesity-related complications (ORC) can vary significantly. We therefore evaluated the efficacy and safety of OMMs in the treatment of obesity and related complications.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: This systematic review and network meta-analysis included randomized clinical trials (RCTs) with at least a 48-week treatment period, comparing OMM versus placebo or active comparators in patients with obesity (body mass index; BMI ≥30 kg/m\u003csup\u003e2\u003c/sup\u003e) or overweight (BMI ≥25 kg/m\u003csup\u003e2\u003c/sup\u003e). A Medline and Embase search was performed up to January 31, 2025 for RCTs on OMMs adopted by at least one EASO member country in adults. The primary endpoint was the percentage of total body weight loss (TBWL%) at the end of the study. Secondary endpoints included TBWL% at 1, 2, and ≥3 years, lipid profile, blood pressure, HbA1c, fasting plasma glucose, mental health, serious adverse events (SAE), quality of life, cardiovascular morbidity and mortality, obesity-associated comorbid condition remission, and all-cause mortality. Weighted mean difference and 95% confidence intervals (CI) were estimated for continuous variables. Mantel-Haenzel odds ratios and 95% CIs were estimated for categorical variables, using random effect models. The study was registered with PROSPERO (registration number CRD42024625338).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFindings\u003c/strong\u003e There were 55 clinical trials identified, they included orlistat (n=21), semaglutide (n=12), liraglutide (n=9), tirzepatide (n=6), naltrexone/bupropion (n=5), and phentermine/topiramate (n=2), enrolling 62,861 patients (33,986 and 28,804 with active compound and placebo, respectively). At the primary endpoint (mean follow-up duration 68 weeks), all OMMs showed a significantly greater TBWL% versus placebo (all p\u0026lt;0.0001). The estimated endpoint TBWL% was greater than 10% for semaglutide and tirzepatide. The type of OMM impacted the magnitude of changes in the secondary outcomes examined. Serious adverse effects (SAE) were reported in most studies, and OMMs were not associated with an increased risk of SAE compared to placebo, except for naltrexone/bupropion. Semaglutide was associated with a lower risk of mortality.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterpretation\u003c/strong\u003e: The present findings support the need to tailor OMMs to the presence and severity of ORC, as different OMMs produce varying degrees of weight loss and have differing impacts on specific ORCs.\u003c/p\u003e","manuscriptTitle":"Pharmacological management of obesity in adults: a systematic review and meta-analysis of randomized controlled trials to evaluate the efficacy and safety of obesity management medications","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-23 06:25:14","doi":"10.21203/rs.3.rs-6449183/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-medicine","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nm","sideBox":"Learn more about [Nature Medicine](http://www.nature.com/nm/)","snPcode":"","submissionUrl":"","title":"Nature Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"34975372-81f3-42bc-99df-2f6f0e502ada","owner":[],"postedDate":"April 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":47327537,"name":"Health sciences/Endocrinology/Endocrine system and metabolic diseases/Obesity"},{"id":47327538,"name":"Biological sciences/Drug discovery/Pharmaceutics"}],"tags":[],"updatedAt":"2025-10-03T07:07:33+00:00","versionOfRecord":{"articleIdentity":"rs-6449183","link":"https://doi.org/10.1038/s41591-025-03978-z","journal":{"identity":"nature-medicine","isVorOnly":false,"title":"Nature Medicine"},"publishedOn":"2025-10-02 04:00:00","publishedOnDateReadable":"October 2nd, 2025"},"versionCreatedAt":"2025-04-23 06:25:14","video":"","vorDoi":"10.1038/s41591-025-03978-z","vorDoiUrl":"https://doi.org/10.1038/s41591-025-03978-z","workflowStages":[]},"version":"v1","identity":"rs-6449183","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6449183","identity":"rs-6449183","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}