High Blood Pressure & Cardiovascular Prevention

, Volume 15, Issue 4, pp 231–243 | Cite as

Reduction of Cardiovascular Risk through Angiotensin II Type 1 Receptor Antagonism

Focus on Olmesartan Medoxomil
Review Article


It is well recognized that angiotensin II is involved in the pathogenesis of hypertension. Less well recognized — until recently, at least — is its involvement in the pathogenesis of atherosclerosis. However, it is now evident that angiotensin II promotes oxidative stress, vascular remodelling, inflammation, and the formation of atherosclerotic lesions. These actions, which are mediated almost exclusively by the angiotensin II type 1 (AT1) receptor, can be blocked by administration of angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]). Of the seven ARBs currently in clinical use, olmesartan is one of the most effective. The rapid and consistent antihypertensive efficacy of this drug, which allows a high proportion of patients to achieve their target blood pressure (BP), is associated with beneficial effects on oxidative stress, vascular remodelling, inflammation, and atherosclerotic lesion formation. These effects appear to be independent of the BP-lowering activity of olmesartan. In clinical trials, olmesartan has been shown to control microinflammation in hypertensive patients, to reduce oxidative stress in patients with type 2 diabetes mellitus, and to normalize the wall: lumen ratio of small resistance arteries (a measure of vascular remodelling) in patients with hypertension. Moreover, in a 2-year study involving hypertensive patients with carotid atherosclerosis (the MORE [Multicentre Olmesartan atherosclerosis Regression Evaluation] trial), olmesartan reduced the intima-media thickness of the carotid artery and significantly reduced the volume of large atherosclerotic plaques. These data suggest that olmesartan may reduce cardiovascular risk by simultaneously normalizing BP and reversing the proatherogenic effects of angiotensin II.

Key words

angiotensin II angiotensin receptor antagonist hypertension olmesartan organ protection, cardiovascular disease atherosclerosis 



Prof. Agabiti Rosei has acted as a consultant for Daiichi Sankyo and has received honoraria for speaking at scientific meetings. Medical writing assistance was provided by Dr Phil Jones of Wolters Kluwer Health, funded by Daiichi Sankyo.


  1. 1.
    World Health Organization. Reducing risks, promoting healthy life. The World Health Report. Geneva, World Health Organization, 2002 [online]. Available from URL: http://www.who.int/whr/2002/en/whr02_en.pdf [Accessed 2007 Jul 25]
  2. 2.
    Petersen SP, Peto V, Rayner M, et al. European cardiovascular disease statistics. 2005 ed. European Heart Network, British Heart Foundation [online]. Available from URL: http://www.ehnheart.org/content/default.asp [Accessed 2007 Jul 25]
  3. 3.
    Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998; 351: 1 755–62Google Scholar
  4. 4.
    Adler AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ 2000; 321: 412–9CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360: 1903–13CrossRefPubMedGoogle Scholar
  6. 6.
    Lusis AJ. Atherosclerosis. Nature 2000; 407: 233–41CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Samuelsson OG, Wilhelmsen LW, Pennert KM, et al. The J-shaped relationship between coronary heart disease and achieved blood pressure level in treated hypertension: further analyses of 12 years of follow-up of treated hypertensives in the Primary Prevention Trial in Gothenburg, Sweden. J Hypertens 1990; 8: 547–55CrossRefPubMedGoogle Scholar
  8. 8.
    Task Force for the Management of Arterial Hypertension of the European Society of Hypertension and of the European Society of Cardiology. 2007 Guidelines for the management of arterial hypertension. Eur Heart J 2007; 28: 1462-536Google Scholar
  9. 9.
    Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004; 363: 2022–31CrossRefPubMedGoogle Scholar
  10. 10.
    Weber MA, Julius S, Kjeldsen SE, et al. Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial. Lancet 2004; 363: 2049–51CrossRefPubMedGoogle Scholar
  11. 11.
    Staessen JA, Thijisq L, Fagard R, et al. Effects of immediate versus delayed antihypertensive therapy on outcome in the Systolic Hypertension in Europe Trial. J Hypertens 2004; 22: 847–57CrossRefPubMedGoogle Scholar
  12. 12.
    Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285: 2486-97CrossRefGoogle Scholar
  13. 13.
    De Backer G, Ambrosioni E, Borch-Johnsen K, et al. European guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J 2003; 24: 1601–10CrossRefPubMedGoogle Scholar
  14. 14.
    Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pres- sure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation 2003; 108: 2154–69CrossRefPubMedGoogle Scholar
  15. 15.
    Liao JK. Endothelium and acute coronary syndromes. Clin Chem 1998; 44: 1799–808PubMedGoogle Scholar
  16. 16.
    Dzau VJ, Antman EM, Black HR, et al. The cardiovascular disease continuum validated: clinical evidence of improved patient outcomes, part I - pathophysiology and clinical trial evidence (risk factors through stable coronary artery disease). Circulation 2006; 114: 2850–70CrossRefPubMedGoogle Scholar
  17. 17.
    Zanchetti A. Evidence-based medicine in hypertension: what type of evidence? J Hypertens 2005Google Scholar
  18. 18.
    Turnbull F, Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet 2003; 362: 1527–35CrossRefPubMedGoogle Scholar
  19. 19.
    Law MR, Wald NJ, Morris JK, et al. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ 2003; 326(7404): 1427CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Volpe M, Tocci G. Antihypertensive therapy and cerebrovascular protection. Curr Opin Nephrol Hypertens 2006; 15: 498–504CrossRefPubMedGoogle Scholar
  21. 21.
    Fabia MJ, Abdilla N, Oltra R, et al. Antihypertensive activity of angiotensin II AT1 receptor antagonists: a systematic review of studies with 24h ambulatory blood pressure monitoring. J Hypertens 2007; 25: 1327–36CrossRefPubMedGoogle Scholar
  22. 22.
    Zannad F, Fay R. Blood pressure-lowering efficacy of olmesartan relative to other angiotensin II receptor antagonists: an overview of randomized controlled studies. Fundam Clin Pharmacol 2007; 21: 181–90CrossRefPubMedGoogle Scholar
  23. 23.
    Brewster UC, Setaro JF, Perazella MA. The renin-angiotensin-aldosterone system: cardiorenal effects and implications for renal and cardiovascular disease states. Am J Med Sci 2003; 326: 15–24CrossRefPubMedGoogle Scholar
  24. 24.
    Schmieder RE, Hilgers KF, Schlaich MP, et al. Renin-angiotensin system and cardiovascular risk. Lancet 2007; 369: 1208–19CrossRefPubMedGoogle Scholar
  25. 25.
    Ferrario CM. Role of angiotensin II in cardiovascular disease therapeutic implications of more than a century of research. J Renin Angiotensin Aldosterone Syst 2006; 7: 3–14CrossRefPubMedGoogle Scholar
  26. 26.
    Carey RM, Wang ZQ, Siragy HM. Role of the angiotensin type 2 receptor in the regulation of blood pressure and renal function. Hypertension 2000; 35: 155–63CrossRefPubMedGoogle Scholar
  27. 27.
    Barker TA, Massett MP, Korshunov VA, et al. Angiotensin II type 2 receptor expression after vascular injury: differing effects of angiotensin-converting enzyme inhibition and angiotensin receptor blockade. Hypertension 2006; 48: 942–9CrossRefPubMedGoogle Scholar
  28. 28.
    Yayama K, Hiyoshi H, Imazu D, et al. Angiotensin II stimulates endothelial NO synthase phosphorylation in thoracic aorta of mice with abdominal aortic banding via type 2 receptor. Hypertension 2006; 48: 958–64CrossRefPubMedGoogle Scholar
  29. 29.
    Savoia C, Touyz RM, Volpe M, et al. Angiotensin type 2 receptor in resistance arteries of type 2 diabetic hypertensive patients. Hypertension 2007; 49(2): 341–6CrossRefPubMedGoogle Scholar
  30. 30.
    Givertz MM. Manipulation of the renin-angiotensin system. Circulation 2001; 104: E14–8CrossRefGoogle Scholar
  31. 31.
    Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000; 342: 145–53Google Scholar
  32. 32.
    Dahlöf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359: 995–1003CrossRefPubMedGoogle Scholar
  33. 33.
    ONTARGET Investigators, Yusuf S, Teo KK, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358: 1547–59CrossRefPubMedGoogle Scholar
  34. 34.
    Olsen MH, Wachtell K, Neland K, et al. Losartan but not atenolol reduce carotid artery hypertrophy in essential hypertension: a L I F E substudy. Blood Press 2005; 14: 177–83CrossRefPubMedGoogle Scholar
  35. 35.
    Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345: 851–60CrossRefPubMedGoogle Scholar
  36. 36.
    Parving HH, Lehnert H, Brochner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001; 345: 870–8CrossRefPubMedGoogle Scholar
  37. 37.
    Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861–9CrossRefPubMedGoogle Scholar
  38. 38.
    Keane WF, Lyle PA. Recent advances in management of type 2 diabetes and nephropathy: lessons from the RENAAL study. Am J Kidney Dis 2003; 41Suppl. 3: S22–5CrossRefPubMedGoogle Scholar
  39. 39.
    de Zeeuw D, Remuzzi G, Parving HH, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int 2004; 65: 2309–20CrossRefPubMedGoogle Scholar
  40. 40.
    Miyazaki M, Takai S. Anti-atherosclerotic efficacy of olmesartan. J Hum Hypertens 2002; 16Suppl. 2: S7–12CrossRefPubMedGoogle Scholar
  41. 41.
    Mukai Y, Shimokawa H, Higashi M, et al. Inhibition of renin-angiotensin system ameliorates endothelial dysfunction associated with aging in rats. Arterioscler Thromb Vasc Biol 2002; 22: 1445–50CrossRefPubMedGoogle Scholar
  42. 42.
    Kanematsu Y, Tsuchiya K, Ohnishi H, et al. Effects of angiotensin II type 1 receptor blockade on the systemic blood nitric oxide dynamics in Nomeganitro- L-arginine methyl ester-treated rats. Hypertens Res 2006; 29: 369–74CrossRefPubMedGoogle Scholar
  43. 43.
    Bahlmann FH, de Groot K, Mueller O, et al. Stimulation of endothelial progenitor cells: a new putative therapeutic effect of angiotensin II receptor antagonists. Hypertension 2005; 45: 526–9CrossRefPubMedGoogle Scholar
  44. 44.
    Naya M, Tsukamoto T, Morita K, et al. Olmesartan, but not amlodipine, improves endothelium-dependent coronary dilation in hypertensive patients. J Am Coll Cardiol 2007; 50: 1144–9CrossRefPubMedGoogle Scholar
  45. 45.
    Tsuda M, Iwai M, Li JM, et al. Inhibitory effects of AT1 receptor blocker, olmesartan, and estrogen on atherosclerosis via anti-oxidative stress. Hypertension 2005; 45: 545–51CrossRefPubMedGoogle Scholar
  46. 46.
    Yoshida J, Yamamoto K, Mano T, et al. AT1 receptor blocker added to ACE inhibitor provides benefits at advanced stage of hypertensive diastolic heart failure. Hypertension 2004; 43: 686–91CrossRefPubMedGoogle Scholar
  47. 47.
    Yao L, Kobori H, Rahman M, et al. Olmesartan improves endothelin-induced hypertension and oxidative stress in rats. Hypertens Res 2004; 27: 493–500CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Fliser D, Wagner KK, Loos A, et al. Chronic angiotensin II receptor blockade reduces (intra)renal vascular resistance in patients with type 2 diabetes. J Am Soc Nephrol 2005; 16: 1135–40CrossRefPubMedGoogle Scholar
  49. 49.
    Kadowaki D, Anraku M, Tasaki Y, et al. Effect of olmesartan on oxidative stress in hemodialysis patients. Hypertens Res 2007; 30: 395–402CrossRefPubMedGoogle Scholar
  50. 50.
    Takai S, Jin D, Sakaguchi M, et al. The regressive effect of an angiotensin II receptor blocker on formed fatty streaks in monkeys fed a high-cholesterol diet. J Hypertens 2005; 23: 1879–86CrossRefPubMedGoogle Scholar
  51. 51.
    Jinno T, Iwai M, Li Z, et al. Calcium channel blocker azelnidipine enhances vascular protective effects of AT1 receptor blocker olmesartan. Hypertension 2004; 43: 263–9CrossRefPubMedGoogle Scholar
  52. 52.
    Li Z, Chen XD, Ni SK, et al. Olmesartan inhibits the expression of monocyte chemoattractant protein-1 and tumor necrosis factor-alpha and improves vascular remodeling after vascular injury in mouse. Chin J Traumatol 2004; 7: 56–61PubMedGoogle Scholar
  53. 53.
    Fliser D, Buchholz K, Haller H, et al. Antiinflammatory effects of angiotensin II subtype 1 receptor blockade in hypertensive patients with microinflammation. Circulation 2004; 110: 1103–7CrossRefPubMedGoogle Scholar
  54. 54.
    Matsuo S, Nakae I, Horie M, et al. Effect of angiotensin II receptor blockade on derived central arterial waveforms in hypertension. Jap Pharmacol Ther 2007; 35: 801–7Google Scholar
  55. 55.
    Min LJ, Mogi M, Li JM, et al. Aldosterone and angiotensin II synergistically induce mitogenic response in vascular smooth muscle cells. Circ Res 2005; 97: 434–42CrossRefPubMedGoogle Scholar
  56. 56.
    Liu HW, Iwai M, Takeda-Matsubara Y, et al. Effect of estrogen and AT1 receptor blocker on neointima formation. Hypertension 2002; 40: 451–7CrossRefPubMedGoogle Scholar
  57. 57.
    Porteri E, Rodella L, Rizzoni D, et al. Effects of olmesartan and enalapril at low or high doses on cardiac, renal and vascular interstitial matrix in spontaneously hypertensive rats. Blood Press 2005; 14: 184–92CrossRefPubMedGoogle Scholar
  58. 58.
    Smith RD, Yokoyama H, Averill DB, et al. Reversal of vascular hypertrophy in hypertensive patients through blockade of angiotensin II receptors. J Am Soc Hypertens 2008; 2(3): 165–72CrossRefPubMedGoogle Scholar
  59. 59.
    Garcia JDM, Fernandez-Torres C, Aguila FJ, et al. Effect of olmesartan medoxomil on arterial stiffness in patients with essential hypertension. Med Clin 2007; 128: 726–9CrossRefGoogle Scholar
  60. 60.
    Kato M, Sada T, Chuma H, et al. Severity of hyperlipidemia does not affect antiatherosclerotic effect of an angiotensin II receptor antagonist in apolipoprotein E-deficient mice. J Cardiovasc Pharmacol 2006; 47: 764–9CrossRefPubMedGoogle Scholar
  61. 61.
    van der Hoorn JW, Kleemann R, Havekes LM, et al. Olmesartan and pravastatin additively reduce development of atherosclerosis in APOE*3Leiden transgenic mice. J Hypertens 2007; 25: 2454–62CrossRefPubMedGoogle Scholar
  62. 62.
    Stumpe KO, Agabiti-Rosei E, Scholze J, et al. Carotid intima-media thickness and plaque volume changes following 2-year angiotensin II-receptor blockade: the Multicentre Olmesartan atherosclerosis Regression Evaluation (MORE) study. Ther Adv Cardiovasc Dis 2007; 1: 97–106CrossRefPubMedGoogle Scholar
  63. 63.
    MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart disease, part 1: prolonged differences in blood pressure — prospective observational studies corrected for the regression dilution bias. Lancet 1990; 335: 765–74CrossRefPubMedGoogle Scholar
  64. 64.
    Oparil S, Williams D, Chrysant SG, et al. Comparative efficacy of olmesartan, losartan, valsartan, and irbesartan in the control of essential hypertension. J Clin Hypertens (Greenwich) 2001; 3: 283–91CrossRefGoogle Scholar
  65. 65.
    Smith DH, Dubiel R, Jones M, et al. Use of 24-hour ambulatory blood pressure monitoring to assess antihypertensive efficacy: a comparison of olmesartan medoxomil, losartan potassium, valsartan, and irbesartan. Am J Cardiovasc Drugs 2005; 5: 41–50CrossRefPubMedGoogle Scholar
  66. 66.
    Brunner HR, Stumpe KO, Januszewicz A. Antihypertensive efficacy of olmesartan medoxomil and candesartan cilexetil assessed by 24-hour ambulatory blood pressure monitoring in patients with essential hypertension. Clin Drug Investig 2003; 23: 419–30CrossRefPubMedGoogle Scholar
  67. 67.
    Brunner H, Arakawa K. Antihypertensive efficacy of olmesartan medoxomil and candesartan cilexetil in achieving 24-hour blood pressure reductions and ambulatory blood pressure goals. Clin Drug Invest 2006; 26: 185–93CrossRefGoogle Scholar
  68. 68.
    Giles TD, Robinson TD. Effects of olmesartan medoxomil on systolic blood pressure and pulse pressure in the management of hypertension. Am J Hypertens 2004; 17: 690–5CrossRefPubMedGoogle Scholar
  69. 69.
    Tseng YZ. Applications of 24-hour noninvasive ambulatory blood pressure monitoring. J Formos Med Assoc 2006; 105: 955–63CrossRefPubMedGoogle Scholar
  70. 70.
    Chrysant SG, Weber MA, Wang AC, et al. Evaluation of antihypertensive therapy with the combination of olmesartan medoxomil and hydrochlorothiazide. Am J Hypertens 2004; 17: 252–9CrossRefPubMedGoogle Scholar
  71. 71.
    Stumpe KO, Ludwig M. Antihypertensive efficacy of olmesartan compared with other antihypertensive drugs [published erratum appears in J Hum Hypertens 2003 Dec; 17 (12): 865]. J Hum Hypertens 2002; 16Suppl. 2: S24–8CrossRefPubMedGoogle Scholar
  72. 72.
    Giles TD, Oparil S, Silfani TN, et al. Comparison of increasing doses of olmesartan medoxomil, losartan potassium, and valsartan in patients with essential hypertension. J Clin Hypertens (Greenwich) 2007; 9: 187–95CrossRefGoogle Scholar
  73. 73.
    Oparil S, Silfani TN, Walker JF. Role of angiotensin receptor blockers as monotherapy in reaching blood pressure goals. Am J Hypertens 2005; 18(2): 287–94CrossRefPubMedGoogle Scholar
  74. 74.
    Neutel JM, Smith DH, Silfani TN, et al. Effects of a structured treatment algorithm on blood pressure goal rates in both stage 1 and stage 2 hypertension. J Hum Hypertens 2006; 20: 255–62CrossRefPubMedGoogle Scholar
  75. 75.
    Basile JN, Chrysant S. The importance of early antihypertensive efficacy: the role of angiotensin II receptor blocker therapy. J Hum Hypertens 2006; 20: 169–75CrossRefPubMedGoogle Scholar
  76. 76.
    Michiels C. Endothelial cell functions. J Cell Physiol 2003; 196: 430–43CrossRefPubMedGoogle Scholar
  77. 77.
    Takai S, Kim S, Sakonjo H, et al. Mechanisms of angiotensin II type 1 receptor blocker for anti-atherosclerotic effect in monkeys fed a high-cholesterol diet. J Hypertens 2003; 21: 361–9CrossRefPubMedGoogle Scholar
  78. 78.
    Yokoyama H, Averill DB, Brosnihan KB, et al. Role of blood pressure reduction in prevention of cardiac and vascular hypertrophy. Am J Hypertens 2005; 18: 922–9CrossRefPubMedGoogle Scholar
  79. 79.
    Arishiro K, Hoshiga M, Negoro N, et al. Angiotensin receptor-1 blocker inhibits atherosclerotic changes and endothelial disruption of the aortic valve in hypercholesterolemic rabbits. J Am Coll Cardiol 2007; 49: 1482–9CrossRefPubMedGoogle Scholar
  80. 80.
    Rizzoni D, Palombo C, Porteri E, et al. Relationships between coronary vasodilator capacity and small artery remodeling in hypertensive patients. J Hypertens 2003; 21: 625–32CrossRefPubMedGoogle Scholar
  81. 81.
    Rizzoni D, Porteri E, Boari GE, et al. Prognostic significance of small-artery structure in hypertension. Circulation 2003; 108: 2230–5CrossRefPubMedGoogle Scholar
  82. 82.
    De Ciuceis C, Porteri E, Rizzoni D, et al. Structural alterations of subcutaneous small arteries may predict major cardiovascular events in hypertensive patients. Am J Hypertens 2007; 20: 846–52CrossRefPubMedGoogle Scholar
  83. 83.
    Smith RD, Yokoyama H, Averill DB, et al. The protective effects of angiotensin II blockade with olmesartan medoxomil on resistance vessel remodeling (the VIOS study): rationale and baseline characteristics. Am J Cardiovasc Drugs 2006; 6: 335–42CrossRefPubMedGoogle Scholar
  84. 84.
    Haller H, Viberti GC, Mimran A, et al. Preventing microalbuminuria in patients with diabetes: rationale and design of the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study. J Hypertens 2006; 24: 403–8CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Clinica Medica and Department of MedicineUniversity of BresciaBresciaItaly

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