1. What Do We Now Know? Moderator Deepak L. Bhatt, MD, MPH Professor of Medicine, Harvard Medical School Executive Director of Interventional Cardiovascular Programs Brigham & Women’s Hospital Heart and Vascular Center Boston, Massachusetts A Balanced Therapeutic Approach to CV Risk in T2D

2. Panelists A. Michael Lincoff, MD Director, C5Research, Cleveland Clinic Coordinating Center for Clinical Research Professor of Medicine Department of Cardiovascular Medicine Cleveland Clinic Lerner College of Medicine Cleveland, Ohio Jean-Claude Tardif, MD Director Montreal Heart Institute Research Centre Professor of Medicine University of Montreal Montreal, Canada

3. Learning Objectives Review the latest evidence on PPAR agonists on the management of cardiovascular risk in patients with type 2 diabetes Discuss the efficacy and safety results seen in the latest cardiovascular outcomes clinical trials evaluating glucose-lowering therapies in patients with type 2 diabetes

4. Metabolic Abnormalities Associated With T2D Insulin resistance High triglyceride Low HDL-cholesterol Slightly elevated LDL-cholesterol –Increased small, dense LDL particle concentration Obesity

5. CV Events With PPAR-gamma Agonists Rosiglitazone Meta-analysis a Myocardial infarction (OR) Meta-analysis a Cardiovascular death (OR) Meta-analysis b Myocardial infarction (OR) Meta-analysis of 42 trials c Myocardial ischemia (OR) Data from Nissen and RECORD d Myocardial infarction (OR) Data from Nissen and RECORD d Cardiovascular death (OR) Meta-analysis e Myocardial infarction (HR) BetterWorse Hazard ratio/Odds ratio Pioglitazone PROactive f Primary end point (HR) PROactive f MI, stroke, or death (HR) PROactive MI subgroup g Myocardial infarction (HR) Meta-analysis h MI, stroke, or death (HR) Meta-analysis c MI, stroke, or death (HR) 1 02 a. Nissen SE, et al. N Engl J Med. 2007;356:2457-2471 [1] ; b. Krall RL, et al. Lancet. 2007;369:1995-1996 [2] ; c. US Food and Drug Administration 2007 [3] ; d. Bracken MB, et al. N Engl J Med. 2007;357:937-938 [4] ; e. Singh S, et al. JAMA. 2007;298:1189-1195 [5] ; f. Dormandy JA, et al. Lancet. 2005;366:1279-1289 [8] ; g. Erdmann E, et al. J Am Coll Cardiol. 2007;49:1772-1780 [9] ; h. Lincoff AM, et al. JAMA. 2007;298;1180-1188. [7]

6. Effect of Fibrates on CV Outcomes A Systematic Review and Meta-analysis Jun M, et al. Lancet. 2010;375:1875-1884. [10] Relative Risk (95% CI) VA CO-OP Atherosclerosis (1973)1.35 (0.89-2.07) VA-HIT (1999)0.78 (0.68-0.90) LEADER (2002)0.94 (0.77-1.15) FIELD (2005)0.90 (0.81-0.99) ACCORD (2010)0.94 (0.80-1.09) Overall 0.90 (0.82-1.00); P =.048 (I 2 = 47.0%, Q = 7.55, P =.110) Excluding VA CO-OP Atherosclerosis 0.88 (0.82-0.95); P =.002 (I 2 = 18.6%, Q = 3.7, P =.298)

7. ACCORD Lipid Hazard Ratios for the Primary Outcome 11.3 (2753) 17.3 (456) 10.1 (2284) ACCORD Study Group, et al. N Engl J Med. 2010;362:1563-1574. [14] 31% reduction in events in patients with atherogenic dyslipidemia 20 with T2D and atherogenic dyslipidemia needed to be treated for 5 years to prevent 1 CV event Simvastatin + fenofibrate better 1 02 Simvastatin alone better Overall Triglyceride – HDL-C combination TG ≥ 204 mg/dL + HDL-C ≤ 34 mg/dL All others 10.5 (2765) 12.4 (485) 10.1 (2264) HR (95% CI) P Value for Interaction % of event (no. in group).06 Simvastatin + placebo Simvastatin + fenofibrate Subgroup

8. Pioglitazone Safety Issues Slightly increased risk for bladder cancer a Bone fractures b Fluid retention, edema, risk for decompensation/congestive heart failure c Nesto RW, et al. Circulation. 2003;108:2941-2948. a. Ferwana M, et al. Diabet Med. 2013;30:1026-1032 [15] ; b. Aubert RE, et al. Diabetes Obes Metab. 2010;12:716-721 [17] ; c. Lincoff AM, et al. JAMA. 2007;298;1180-1188. [7]

9. Pioglitazone Meta-analysis Heart Failure & MI Lincoff AM, et al. JAMA. 2007;298;1180-1188. [7] MI Death/MI Serious HF Death/serious HF Pioglitazone better 1 02 Control better HR (95% CI) End Point

10. Dual PPAR  /  Agonists Past Development Programs Phase of Investigation Program Outcome Reasons for Termination Tesaglitazar3 Terminated May, 2006 Data from ~ 3000 patients Increased creatinine; uncertain risk: benefit a,b Muraglitazar3 Terminated May, 2006 Data from 3725 patients Excess CV events in pooled trials c a. Ratner RE, et al. Diabetes Vasc Dis Res. 2007;4:214-221 [18] ; b. Hamrén B, et al. J Clin Pharmacol. 2012;52:1317-1327 [19] ; c. Nissen SE, et al. JAMA. 2005;294:2581-2586. [1]

11. AleCardio Aleglitazar (PPAR  /  Agonist) in Patients With T2D and ACS Phase 3, double-blind, parallel, randomized trial in patients with recent ACS and T2D Enrolled 7226 patients Treatment duration: at least 2.5 years Placebo (+ SC) Aleglitazar 150  g (+ SC) Primary efficacy: Time to 1 st occurrence of CV death, nonfatal MI, or nonfatal stroke Secondary efficacy : CV death, MI, stroke, or hospitalization for ACS Principal safety: Hospitalization due to heart failure and changes in renal function Superiority: Event-driven (950 primary end point events) Inclusion Criteria: Adults > 18 years of age T2D Hospitalization for ACS event and randomization up to 12 weeks after index event Lincoff AM et al. JAMA. 2014;311:1515-1525. [16]

12. AleCardio Efficacy and Safety Outcomes Primary efficacy Secondary efficacy Hospitalization for HF Gastrointestinal hemorrhage Bone fracture Aleglitazar better 102 Placebo better HR (95% CI)End Point Lincoff AM et al. JAMA. 2014;311:1515-1525. [16]

13. AleCardio Glycemic Control and Lipoprotein Effects Mean Change From Baseline, % HbA 1c HDL-C TG LDL-C

14. Genes Regulated by Glitazones Sears DD, et al. Biochem Biophys Res Commun. 2007;364:515-521. [21] The number of genes uniquely regulated by a glitazone is contained in the nonoverlapping regions of each circle Repressed (N = 179) 5147 8 56 36 26 Pioglitazone - 70Rosiglitazone - 140 Troglitazone - 126 Pioglitazone - 52Rosiglitazone - 65 Activated (N = 147) Troglitazone - 122 8215 4 38 10 70

15. Older Antidiabetic Drugs and CV Benefit/Harm Sulfonylureas – May facilitate ischemic preconditioning in the diabetic heart (animal data) a – Class warning for possible increased CV mortality b Metformin – Potential for risk reduction in MI and death from any cause in overweight patients c Rosiglitazone – Potential increased risk of MI d – Class warning for congestive heart failure e Pioglitazone – Potential for risk reduction in all-cause mortality, nonfatal MI, or stroke f – Class warning for congestive heart failure g a. Hausenloy DJ, et al. J Cardiovasc Pharmacol Ther. 2013;18:263-269 [22] ; b. US Food and Drug Administration 2013 [23] ; c. UK Prospective Diabetes Study. Lancet. 1998;352:854-865 [24] ; d. Nissen SE, et. N Engl J Med. 2007;356:2457-2471 [1] ; e. Avandia [package insert] [32]; f. Dormandy JA, et al. Lancet. 2005;366:1279-1289 [8] ; f. Actos® [package insert]. [33]

16. SAVOR-TIMI 53 Clinical End Points: Saxagliptin (DPP4 Inhibitor) vs Placebo Scirica BM et al. N Engl J Med. 2013;369:1317-1326. [25] Primary efficacy: CV death, MI, or stroke Secondary efficacy: CV death, MI, stroke, hospitalization for UA, HF, or coronary revascularization Death from any cause Death from CV causes MI Ischemic stroke Hospitalization for UA Hospitalization for HF Hospitalization for coronary revascularization Doubling of creatinine level, initiation of dialysis, renal transplantation, or creatinine > 6.0 mg/dL (530 μmol/L) Hospitalization for hypoglycemia HR (95% CI)End Point 021 Saxagliptin betterPlacebo better

17. Scirica BM et al. Circulation. 2014 [Epub ahead of print]. [26] SAVOR-TIMI 53 Hospitalization for Heart Failure Stratified by NT-proBNP Quartiles Quartiles of NT- proBNP (pg/mL)Saxagliptin, %Placebo, %HR (95% CI) P Value Q1 (5-64) 0.7 1.04 (0.04-26.30).98 Q2 (65-141) 1.10.4 1.82 (0.86-4.09).12 Q3 (1412-333) 2.22.0 0.94 (0.57-1.55).82 Q4 (333-46,627) 11.08.9 1.31 (1.04-1.66).02

18. Scirica BM et al. N Engl J Med. 2013;369:1317-26. [25] SAVOR-TIMI 53 Safety End Points End Point Saxagliptin N = 8280, % Placebo N = 8212, %P Value Bone fracture2.9 1.00 Cancer3.94.4.15 Any pancreatitis0.3.77 Any liver abnormality0.70.8.28 Any hypoglycemia15.313.4<.001 Major2.11.7.047 Minor14.212.5.002

19. EXAMINE Safety End Points: Alogliptin (DPP-4 Inhibitor) vs Placebo White WB, et al. N Engl J Med. 2013; 369:1327-1335. Primary end point: death from CV causes, nonfatal MI, or nonfatal stroke Secondary end point: death from CV causes, nonfatal MI, nonfatal stroke, or urgent revascularization due to unstable angina within 24 hours after hospital admission HR (95% CI)End Point Primary end point Components of primary end point Death from CV causes Nonfatal MI Nonfatal stroke Principal secondary end point Other end points Death from any cause Death from CV causes

20. EXAMINE Heart Failure Outcomes Zannad F, et al. J Am Coll Cardiol. 2014;63(12S). Composite CV outcome: first occurrence of all-cause mortality, nonfatal MI and stroke, urgent revascularization due to unstable angina, and hospitalization for HF HR (95% CI)Outcome Composite CV outcome Hospitalization for HF Composite of CV death and hospitalization due to HF CV death Hospitalization for HF

21. Mechanism of Heart Failure Fluid retention as evidenced by –Weight gain with PPARs –Reduction in glomerular filtration and creatinine clearance that is reversible on discontinuing PPAR Other as yet unknown mechanism

22. Ongoing CVD Outcomes Trials in Type 2 Diabetes StudyIntervention Estimated EnrollmentEstimated Duration EXSCEL Exenatide once weekly vs placebo 95006/2010–3/2017 FREEDOM- CVO ITCA 650 (exenatide) vs placebo 200003/2013–07/2018 LEADERLiraglutide vs placebo93408/2010–1/2016 ELIXALixisenatide vs placebo60006/2010–10/2013 REWINDDulaglutide vs placebo96227/2011–4/2019 TECOSSitagliptin vs placebo14,00012/2008–12/2014 CAROLINALinagliptin vs glimepiride600010/2010–9/2018 CARMELINALinagliptin vs placebo830007/2013–01/2018 ACEAcarbose vs placebo750002/2009-10/2014 CANVASCanagliflozin vs placebo433512/2009-06/2018

23. Clinical Trial Design Considerations Current trial designs – Follow-up not long enough to show CV risk reduction – Focus on CV safety and not CV benefit Enrollment of high-risk patients to show occurrence of events quickly to demonstrate noninferiority Future trial considerations to show CV benefit – Larger trials – Longer follow-up – Population not at high ischemic risk No recent ACS No previous MI No previous stroke – Population with early atherosclerotic disease

24. AlePrevent Aleglitazar in Patients With Stable CVD and Glucose Abnormalities Phase 3B, double-blind, parallel, randomized trial in patients with stable CVD and glucose abnormalities Target sample size = 19,000 patients Study duration: 5 years Inclusion Criteria: Adults ≥ 40 years Stable CVD Established T2D/evidence of glucose abnormalities Placebo (+ SC) Aleglitazar 150  g (+ SC) Primary: Time to 1 st occurrence of CV death, nonfatal MI, or nonfatal stroke Secondary 1: Time to 1 st occurrence of CV death, nonfatal MI, or nonfatal stroke in subgroups with or without evidence of T2D at baseline Secondary 2: Time to 1 st occurrence of all-cause mortality, nonfatal MI, or nonfatal stroke in subgroups with or without evidence of T2D at baseline Clinicaltrials.gov. NCT01715818. [29]

25. Newer Antidiabetic Drugs & CV Risk Reduction GLP-1 receptor agonists – Weight loss a – Reduction in blood pressure b SGLT2 inhibitors c – Weight loss – Reduction in blood pressure a. Pinelli NR, et al. Ann Pharmacother. 2011;45:850-860 [31] ; b. Wang B, et al. Diabetes Obes Metab. 2013;15:737-749 [34] ; c. Kaushal S. N Am J Med Sci. 2014;6:107-113. [30]

26. Concluding Remarks Aggressive lipid management with – Statins – Newer agents: PCSK9 inhibitors and CEPT inhibitors Other CV risk factor management – Obesity – Hypertension – Inflammation Lifestyle modification

27. Abbreviations ACCORD = Action to Control Cardiovascular Risk in Diabetes) ACS = acute coronary syndromes AleCardio = Safety and Efficacy Study to Evaluate the Potential of Aleglitazar to Reduce Cardiovascular Risk in Coronary Heart Disease Patients With a Recent Acute Coronary Syndrome Event and Type 2 Diabetes Mellitus AlePrevent = Aleglitazar in Patients With a Recent Acute Coronary Syndrome and Type 2 Diabetes Mellitus BNP = brain natriuretic peptide C = cholesterol CANVAS = Canagliflozin Cardiovascular Assessment Study CARMELINA = Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus at High Vascular Risk CAROLINA = Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes CETP = cholesterylester transfer protein CI = confidence interval CV = cardiovascular CVD = cardiovascular disease DPP4 = dipeptidyl peptidase-4

28. Abbreviations (cont) ELIXA = Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With AVE0010 [Lixisenatide] EXAMINE = Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome EXSCEL = Exenatide Study of Cardiovascular Event Lowering FIELD = Fenofibrate Intervention and Event Lowering in Diabetes FREEDOM-CVO = Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease-CVO GLP-1 = glucagon-like peptide-1 HbA1c = hemoglobin A1c HDL = high-density lipoprotein HF = heart failure HR = hazard ratio LDL = low-density lipoprotein LEADER = Lower Extremity Arterial Disease Event Reduction MI = myocardial infarction NT-proBNP = N-terminal of the prohormone brain natriuretic peptide OR = odds ratio

29. Abbreviations (cont) PCSK9 = proprotein convertase subtilisin/kexin type 9 PPAR = peroxisome proliferator-activated receptor PROactive = Prospective Pioglitazone Clinical Trial in Macrovascular Events RECORD = Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes REWIND = Researching Cardiovascular Events With a Weekly Incretin in Diabetes SAVOR-TIMI 53 = Does Saxagliptin Reduce the Risk of Cardiovascular Events When Used Alone or Added to Other Diabetes Medications- Thrombolysis in Myocardial Infarction SC = subcutaneous SGLT2 = sodium-glucose co-transporter 2 T2D = type 2 diabetes TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin TG = triglyceride UA = unstable angina VA CO-OP = Veterans Administration Cooperative Study Group VA-HIT = Veterans Affairs High-Density Lipoprotein Intervention Trial

30. References 1. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457-2471. 2. Krall RL. Cardiovascular safety of rosiglitazone. Lancet. 2007;369:1995-1996. 3. US Food and Drug Administration. NDA 21-071 Supplement 022 FDA Meta- Analysis. Advisory Committee Briefing Document. Cardiovascular Safety of Rosiglitazone. http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4308b1-01- sponsor-backgrounder.pdf Accessed September 18, 2014. 4. Bracken MB. Rosiglitazone and cardiovascular risk. N Engl J Med. 2007;357:937-938. 5. Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA. 2007;298:1189-1195. 6. Home PD, Pocock SJ, Beck-Nielsen H, et al; RECORD Study Team. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet. 2009;373:2125-2135.

31. References (cont) 7. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007;298:1180-1188. 8. Dormandy JA, Charbonnel B, Eckland DJ, et al; PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366:1279-1289. 9. Erdmann E, Dormandy JA, Charbonnel B, et al; PROactive Investigators. The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction: results from the PROactive (PROactive 05) Study. J Am Coll Cardiol. 2007;49:1772-1780. 10. Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet. 2010;375:1875-1884.

32. References (cont) 11. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987;317:1237-1245. 12. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med. 1999;341:410-418. 13. Keech A, Simes RJ, Barter P, et al; FIELD study investigators. Effects of long- term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366:1849-1861. 14. ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563-1574.

33. References (cont) 15. Ferwana M, Firwana B, Hasan R, et al. Pioglitazone and risk of bladder cancer: a meta-analysis of controlled studies. Diabet Med. 2013;30:1026-1032. 16. Lincoff AM, Tardif JC, Schwartz GG, et al; AleCardio Investigators. Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus: the AleCardio randomized clinical trial. JAMA. 2014;311:1515-1525. 17. Aubert RE, Herrera V, Chen W, et al. Rosiglitazone and pioglitazone increase fracture risk in women and men with type 2 diabetes. Diabetes Obes Metab. 2010;12:716-721. 18. Ratner RE, Parikh S, Tou C; GALLANT 9 Study Group. Efficacy, safety and tolerability of tesaglitazar when added to the therapeutic regimen of poorly controlled insulin-treated patients with type 2 diabetes. Diabetes Vasc Dis Res. 2007;4:214-221.

34. References (cont) 19. Hamrén B, Ohman KP, Svensson MK, Karlsson MO. Pharmacokinetic- pharmacodynamic assessment of the interrelationships between tesaglitazar exposure and renal function in patients with type 2 diabetes mellitus. J Clin Pharmacol. 2012;52:1317-1327. 20. Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA. 2005;294:2581-2586. 21. Sears DD, Hsaio A, Ofrecio JM, et al. Selective modulation of promoter recruitment and transcriptional activity of PPAR? Biochem Biophys Res Commun. 2007;364:515-521. 22. Hausenloy DJ, Wynne AM, Mocanu MM, Yellon DM. Glimepiride treatment facilitates ischemic preconditioning in the diabetic heart. J Cardiovasc Pharmacol Ther. 2013;18:263-269.

35. References (cont) 23. US Food and Drug Administration. Code of Federal Regulations Title 21. Labeling for oral hypoglycemic drugs of the sulfonylurea class. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=310.51 7. Updated April 1, 2013. Accessed September 18, 2014. 24. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-865. 25. Scirica BM, Bhatt DL, Braunwald E, et al; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317-1326. 26. Scirica BM, Braunwald E, Raz I, et al; for the SAVOR-TIMI 53 Steering Committee and Investigators. Heart Failure, Saxagliptin and Diabetes Mellitus: Observations from the SAVOR - TIMI 53 Randomized Trial. Circulation. 2014 Sep 4. pii: CIRCULATIONAHA.114.010389. [Epub ahead of print]

36. References (cont) 27. White WB, Cannon CP, Heller SR, et al; EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327-1335. 28. Zannad F, Cannon C, Cushman W, et al. Alogliptin in patients with type 2 diabetes after acute coronary syndromes: heart failure outcomes and cardiovascular safety in heart failure patients. J Am Coll Cardiol. 2014;63(12_S):A117. 29. ClinicalTrials.gov. A Study on The Potential of Aleglitazar to Reduce Cardiovascular Risk in Patients With Stable Cardiovascular Disease and Glucose Abnormalities. NCT01715818. http://www.clinicaltrials.gov/ct2/show/NCT01715818. Accessed September 18, 2014. 30. Kaushal S, Singh H, Thangaraju P, Singh J. Canagliflozin: a novel SGLT2 inhibitor for type 2 diabetes mellitus. N Am J Med Sci. 2014;6:107-113.

37. References (cont) 31. Pinelli NR, Hurren KM. Efficacy and safety of long-acting glucagon-like peptide- 1 receptor agonists compared with exenatide twice daily and sitagliptin in type 2 diabetes mellitus: a systematic review and meta-analysis. Ann Pharmacother. 2011;45:850-860. 32. Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 33. Actos [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; 2013. 34. Wang B, Zhong J, Lin H, et al. Blood pressure-lowering effects of GLP-1 receptor agonists exenatide and liraglutide: a meta-analysis of clinical trials. Diabetes Obes Metab. 2013;15:737-749.