Nephrological aspects of congestivecardiac failure


如何引用文章

全文:

作者简介

S Moiseev

V Fomin

参考

  1. Беленков Ю. Е., Мареев В. Ю. Принципы рационального лечения сердечной недостаточности. М.: МедиаМедика; 2000.
  2. Mosted A., Hoes A. W., de Bruyne М. С. et al. Prevalence of heart failure and left ventnricular dysfunction in the general population. Eur. Heart J. 1999; 20: 447-455 .
  3. ESC Task Force for the diagnosis and treatment of chronic heart failure Guidelines for the diagnosis and treatment of chronic heart failure. Ibid. 2001; 22: 1527-1560.
  4. Моисеев В. С., Сумароков А. В. Болезни сердца. М.: Универсум Паблишинг; 2001.
  5. Carrie В. J., Huberman М., Schroeder J. S., Myers B. D. Albuminuria and the permselective properties of the glomerulus in cardiac failure. Kidney Int. 1980; 17: 507-514.
  6. Eiskjaer H., Bagger J. P., Mogensen С. E. et al. Enhanced urinary excretion of albumin in congestive heart failure: effect of ACE-inhibition. Scand. J. Clin. Lab. Invest. 1992; 52: 193- 199.
  7. Berton G., Citro Т., Cordiano R. et al. Urinary albumin excretion increases during an acute myocardial infarct especially in patients who develop heart failure. G. Ital. Cardiol. 1995; 25: 999-1009.
  8. Albright R., Brensilver J., Cortell S. Proteinuria in congestive heart failure. Am. J. Nephrol. 1983; 3: 272-275.
  9. Михаилов А. А. Почки при сердечной недостаточности. Вкн.- Тареев Е. М. (ред.) Основы нефрологии. М.: Медицина; 1972. 555-560.
  10. Kada P. A., Raghavan С., Hassan R. et al. Nephrotic-range proteinuria associated with right atrial myxoma. Clin. Nephrol. 1992; 37: 294-296.
  11. Bortolotto L. A., Sdva H. В., Galvao L. F. et al. Proteinuria in patients with congestive heart failure. Role of arterial hypertension. Arq. Bras. Cardiol. 1993; 60: 243-245.
  12. Schrier R. W. Pathogenesis of sodium and water retention in high-output and low-output cardiac failure, nephrotic syndrome, cirrhosis and pregnancy. N. Engl. J. Med. 1988; 319: 1065-1072.
  13. Abraham W. Т., Schrier R. W. Renal function in congestive heart failure. In: Greenberg A., ed. Primer on kidney diseases. 2"ded. San-Diego: Academic Press; 1998. 183-187.
  14. Hall W. D. Abnormalities of kidney function as a cause and a consequence of cardiovascular disease. Am. J. Med. Sci. 1999; 317: 176-182
  15. Matsusaka I., Hymes J., Ischikawa 1. Angiotensin in progressive renal diseases: theory and practice. J. Am. Soc. Nephrol. 1996; 7: 2025-2043.
  16. Wolf G. Angiotensin II: a pivotal factor in the progression of renal disease. Nephrol. Dial. Transplant. 1999; 14 (suppl. 1): 42-44.
  17. Matsushima H., Yoshida H., Machiguchi T. et al. Urinary albumin and TGF-1 levels as renal damage indices in patients with congestive heart failure. Clin. Exp. Nephrol. 2002; 6: 21-29.
  18. Yoshida H., Yashiro M., Liang P. et al. Mesangiolytic glomerulopathy in severe congestive heart failure. Kidney Int. 1998; 53: 880-891.
  19. Goldfarb M., Abassi Z., Rosen S. Compensated heart failure predisposes to outer medullary tubular injury: studies in rats. Ibid. 2001; 60: 607-613.
  20. Remuzzi G., Bertani T. Pathophysiology of progressive nephropathies. N. Engl. J. Med. 1998; 339: 1448-1456.
  21. Ruggenenti P., Schiepatti A., Remuzzi G. Progression, remission, regression of chronic renal diseases. Lancet 2001; 357: 1601 - 1608.
  22. Locatelli F., Carbans I., Maschio G. et al. Long-term progression of chronic renal insufficiency in the AIPRI Extension Study. Kidney Int. 1997; 52 (suppl. 63): 63-66.
  23. Ruggenenti P., Perna A., Gherardi G. et al. Renoprotective properties of ACE-inhibitors in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet 1999; 354: 359-364.
  24. Parving H.-H., 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: 870-878.
  25. Pitt В., Poole-Wilson P. A., Segal R. et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomized trial - the Losartan Heart Failure Survival Study ELITE II. Lancet 2000; 355: 1582- 1587.
  26. Cohn J., Tognoni G. for the Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N. Engl. J. Med. 2001; 345: 1667-1677.
  27. Komajada M. Are angiotensin II receptor blockers indicated in chronic heart failure? Heart 2002; 87: 1-2 .
  28. Плетнев Д. Д. Болезни сердца М.; Л.: 1936.
  29. Szatalowitz У. L., Arnbold P. E., Chaimpvitz С. et al. Radio immunoassay of plasma arginine vasopressin in hyponatriemic patients with congestive heart failure. N. Engl. J. Med. 1981: 305: 263-266.
  30. Lee W. H., Packer M. Prognostic improtance of serum sodium concentrations and its modification by angiotensin converting-enzyme inhibition in patients with severe chronic heart failure. Circulation 1986; 73: 257-267.
  31. Kaira P. R., Anker S. D., Coats A. J. S. Water and sodium regulation in chronic heart failure: the role of natriuretic peptides and vasopressin. Cardiovasc. Res. 2001; 51: 495-509.
  32. Carmichael M. C., Kumar R. Molecular biology of vasopressin receptors. Semin. Nephrol. 1994; 14: 341-348.
  33. Nielsen S., Chou С. L., Marples D. et al. Vasopressin increases water permeability of kidney collecting duct by inducing translocation of aquaporin-CD water channels to plasma membrane. Proc. Natl. Acad. Sci. USA 1995; 92: 1013-1017.
  34. Teris J., Ecelbarger С. A., Nielsen S., Knepper M. A. Long-term regulation of four renal aquaporins in rat. Am. J. Physiol. 1996; 271: F4I4-F422.
  35. Agre P., Preston J. M., Smith B. L. et al. Aquaporin CHIP: the archetypal molecular water channel. Ibid. 1993; 265: F463 - F476.
  36. Nielsen S., Kwon T.-W., Monster B. et al. Physiology and pathophysiology of renal aquaporins. J. Am. Soc. Nephrol. 1999; 10: 647-663.
  37. Kwon T. H., Hager H., Nejsum L. N. et al. Physiology and pathophysiology of renal aquaporins. Semin. Nephrol. 2001; 21: 231-238.
  38. Knepper M. A. Molecular physiology of urinary concentrating mechanism: regulation of aquaporin water channels by vasopressin. Am. J. Physiol. 1997; 272: F3-F12.
  39. Deen P. M., Verdjik M. A., Knoers N. V. Requirement of human renal water channel aquaporin-2 for vasopressin-dependent concentration of urine. Science 1994; 264: 92-95 .
  40. DiGiovanni S. R., Nielsen S., Christensen E. I., Knepper M. A. Regulation of collecting duct water channel expression by vasopressin in Brattleboro rat. Proc. Nail. Acad. Sci. USA 1994; 91: 8984-8988.
  41. Nielsen S., Terris J., Andersen D. et al. Congestive heart failure in rats is associated with increased expression and targeting of aquaporin-2 water channel in collecting duct. Ibid. 1997; 94: 5450-5455.
  42. Fshikawa S. Urinary excretion of aquaporin-2 in pathological states of water metabolism. Ann. Med. 2000; 32: 90-93.
  43. Schrier R. W., Martin P. Y. Recent advances in the understanding of water metabolism in heart failure. Adv. Exp. Med. Biol. 1998; 449: 415-426.
  44. Frokiaer J., Marples D., Knepper M. A., Nielsen S. Pathophysiology of aquaporin-2 in water balance disorders. Am. J. Med. Sci. 1998; 316: 291-299.
  45. Xu D. L., Martin P. Y., Ohara M. et al. Upregulation of aquaporin-2 water channel expression in chronic heart failure rat.J. Clin. Invest. 1997; 99: 1500-1505.
  46. Martin P. Y. Recent advances in the understanding of water metabolism in heart failure (involvement of aquaporin). Kidney Blood Pressure Res. 2000; 23: 193 - 194.
  47. Xu D., Yin X., Hui H. et al. Urinary excretion of aquaporin-2 water channel protein in chronic heart failure rats. Chin. Med. J. 2001; 114: 899-901.
  48. Wong N. L., Tsui J. K. Upregulation of vasopressin V2 and aquaporin 2 in the inner medullary collecting duct of cardiomyopathy hamsters is attenuated by enalapril treatment. Metabolism 2002; 51: 970-975.
  49. Laski M. E., Pressley T. A. Aquaporin mediated water flux as a target for diuretic development. Semin. Nephrol. 1999; 19: 533-550.
  50. Ohnishi A., Orita Y., Takagi N. et al. Aquaretic effect of a potent, orally active, nonpeptide V2 antagonist in men. J. Pharmacol. Exp. Ther. 1995; 272: 546-551.
  51. Inoue Т., Ohnishi A., Matsuo A. et al. Therapeutic and diagnostic potential of a vasopressin-2 antagonist for impaired water handling in cirrhosis. Clin. Pharmacol. Ther. 1998; 63: 561- 570.
  52. Saito Т., Ishikawa S., Abe K. et al. Acute aquaresis by the nonpeptide arginine vasopressin (AVP) antagonist OPC-31260 improves hyponatriemia in patients with syndrome of inappropriate secretion of antidiuretic hormone (SIADH). J. Clin. Endocrinol. Metab. 1997; 82: 1054-1057.
  53. Gros P., Palm С. The treatment of hyponatraemia using vasopressin antagonists. Exp. Physiol. 2000; 85S: 7S-18S.
  54. Yatsu Т., Tomura X., Tahara A. et al. Cardiovascular and renal effects of conivaptan hydrochloride (YM087), a vasopressin VIA and V2 receptor antagonist, in dogs with pacing-induced congestive heart failure. Eur. J. Pharmacol. 1999; 376: 239- 246.
  55. Udelson J. E., Smith W. В., Hendrix G., H. et al. Acute hemodynamic effects of conivaptan, a dual V(1A) and V(2) vasopressin receptor antagonist, in patients with advanced heart failure. Circulation 2001; 104: 2417-2423.
  56. Martin P.-Y., Abraham W. Т., Lieming X. et al. Selective V2- receptor vasopressin antagonist decreases urinary aquaporin-2 excretion in patients with chronic heart failure. J. Am. Soc. Nephrol. 1999; 10: 2165-2170.
  57. Wong L., Verbalis J. Vasopressin V2 receptor antagonists. Cardiovasc. Res. 2001; 51: 391-402.
  58. Wilkins M. R., Redondo J., Brown L. A. The natriuretic-peptide family. Lancet 1997; 349: 1307-1310.
  59. Kaira P. R., Anker S. D., Coats A. J. S. Water and sodium regulation in chronic heart failure: the role of natriuretic peptides and vasopressin. Cardiovasc. Res. 2001; 51: 495-511.
  60. Bold A. J., Borenstein H. В., Veress А. Т., Sonnenberg H. A. A rapid and potent natriuretic responce to intravenous injection of atrial myocardial extract in rats. Life Sci. 1981; 28: 89-94.
  61. Sudoh Т., Kangawa K., Miniamino N., Matsuo H. A new natriuretic peptide in porcine brain. Nature 1988; 332: 78-81.
  62. Sudoh Т., Miniamino N., Kangawa K., Matsuo H. C-type natriuretic peptide (CNP): a new member of the natriuretic peptide family identified in porcine brain. Biochem. Biophys. Res. Commun. 1990; 168: 863-870.
  63. Suga S., Nakao K., Hosoda K. et al. Receptor selectivity ofnatriuretic peptide family, atrial natriuretic peptide, brain natriuretic peptide and C-type netriuretic peptide. Endocrinology 1992; 130: 229-239.
  64. Grandclement В., Morel G. Ultrastructural characterization of atrial natriuretic peptide receptors (ANP-R) mRNA expression in rat kidney cortex. Biol. Cell 1998: 90: 213-222.
  65. Almeida P. M., Suzuki M., Scarborough R. M. et al. Clearance function of type С receptors of atria natriuretic factor in rats.Am. J. Physiol. 1989; 256: R469-R475.
  66. Харманов В. Н. Предсердный натрий-уретический гормон. Тер. арх. 1987; 59 (11): 142-147.
  67. Itoh К., Nonoguchi И., Shiraishi N., Tomita К. Gene regulation of atrial natriuretic peptide A, B, and С receptors in rat glomeruli. Exp. Nephrol. 1999; 7: 328-336.
  68. McDonagh T. A., Robb S. D., Murdoch D. R. et al. Biochemical detection of left-ventricular systolic dysfunction. Lancet 1998; 351: 9-13.
  69. Troughton R. W., Frampton С. M., Yandle T. G. et al. Treatment of heart failure guided by plasma aminoterminal peptide (N-BNP) concentrations. Ibid. 2000; 355: 1126-1130.
  70. Lerman A., Gibbons R. J., Rodehefner R. J. et al. Circulating N-terminal atrial natriuretic peptide as a marker for symptomless left-ventricular dysfunction. Ibid.1993; 341: 1105-1109.
  71. Nagaya N., Nishikimi Т., Goto Y. et al. Plasma brain natriuretic peptide is a biochemical marker for the prediction of progresive ventricular remodeling after cute myocardial infarction.Am. Heart J. 1998; 135: 21-28.
  72. Mills R. M., LeJemtel Т. Н., Horton D. P. et al. Sustained hemodynamic effects of an infusion of nesiritide (human b-type natriuretic peptide) in heart failure: a randomized, doubleblind, placebo-controlled trial. Natrecor Study Group. J. Am. Coll. Cardiol. 1999; 34: 155-162.
  73. Colucci W. S., Elkayam U., Horton D. P. et al. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. Nesiritide Study Group. N. Engl. J. Med. 2000; 343: 246-253.
  74. Aronson D., Burger A. J. Intravenous nesiritide (human b-type natriuretic peptide) reduces plasma endothelin-1 levels in patients with decompensated heart failure. Am. J. Cardiol. 2002- 15: 435-438.
  75. Rahman S. N., Kim G. E., Mathew A. S. et al. Effects of atrial natriuretic peptide in clinical acute renal failure. Kidney Int 1994; 45: 1731-1738.
  76. Algren R. L., Marbury T. C., Rahman S. N. et al. Anaritide in acute tubular necrosis. Auriclin Anaritide Acute Renal Failure Study Group. N. Engl. J. Med. 1997; 336: 828-834.
  77. Meyer M., Pfarr E., Schrimer G. et al. Therapeutic use of the natriuretic peptide ularitide in acute renal failure. Renal. Failure 1999; 21: 85-100.
  78. Wiebe K., Meyer M., Wahlers T. et al. Acute renal failure following cardiac surgery is reverted by administration of Urodilatin (INN: Ularitide). Eur. J. Med. Res. 1996; I: 259-265.
  79. Meyer M., Wiebe K., Wahlers T. et al. Urodilatin (INN: ularitide) as a new drug for the therapy of acute renal failure following cardiac surgery. Clin. Exp. Pharmacol. Physiol. 1997; 24: 374-376.
  80. Ikram H., McClean D. R., Mehta S. et al. Long-term beneficial hemodynamic and neurohormonal effects of vasopeptidase inhibition with omapatrilat in heart failure. J. Am. Coil. Cardiol. 1999; 33: 185A.
  81. McClean D. R., Ikram Е., Gartick A. H. et al. The clinical, cardiac, renal, arterial and neurohormonal effects of omapatrilat a vasopeptidase inhibitor, in patients with chronic heart failure. Ibid. 2000; 36: 479-486.
  82. Ska D., Liao W., Gehr T. W. B. et al. Disposition and safety of omapatrilat in subjects with renal impairment. Clin. Pharmacol. Ther. 2000; 68: 261-269.
  83. Cao Z., Burrell L. M., Tikkanen I. et al. Vasopeptidase inhibition attenuates the progression of renal injury in subtotal nephrectomized rats. Kidney Int. 2001; 60: 715-721.
  84. Rouleau J. L., Pfeffer M. A., Stewart D. J. et al. Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomized trial. Lancet 2000; 356: 615-620.
  85. Weber M. A. Vasopeptidase inhibitors. Lancet 2001; 358: 1525-1527.
  86. The CONSENSUS Trial Study Group. Effects of enalapnl on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N. Engl. J. Med. 1987; 316: 1429-1435.
  87. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. Ibid. 1991; 325: 293-302.
  88. Flather M., Yusuf S., Kober L. et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-inhibitor Myocardial Infarction Collaborative Group. Lancet 2000; 355: 1575-1581.
  89. Ljungman S., Kjekshus J., Swedberg K. Renal function in severe congestive heart failure during treatment with enalapril (the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) Trial). Am. J. Cardiol. 1992; 70: 479-487.
  90. Kostis J. В., Shelton В., Gosselin G. et al. Adverse effects of enalapril in the studies of left ventricular dysfunction (SOLVD). SOLVD Investigators. Am. Heart J. 1996; 131: 350-355.
  91. Ryden I., Armstrong P. W., Cleland J. G. F. et al. Efficacy and safety of high-dose lisinopril in chronic heart failure patients at high cardiovascular risk, including those with diabetes mellitus; results from the ATLAS trial. Eur. Heart. J. 2000; 21: 1967- 1978.
  92. Opie L. H. Angiotensin converting enzyme inhibitors: the advance continues. 3'" ed. New York: UCT Press; 1999.
  93. Maxwell A. P., Ong H. Y., Nicholls D. P. Influence of progressive renal dysfunction in chronic heart failure. Eur. J. Heart Failure 2002; 4: 125-130.
  94. Heiat A., Gross С. P., Krumholz H. M. Representation of the elderly, women, and minorities in heart failure clinical trials. Arch. Intern. Med. 2002; 162: 1682-1688.
  95. Alcazar J. M., Rodicio J. L. Ischemic nephropathy. Am. J. Kidney Dis. 2000; 36: 883-893.
  96. Al Shohaib S., Raweily E. Acute tubular necrosis due to captopril. Am. J. Nephrol. 2000; 20: 149-152.
  97. Chan T. Y., Critchley J. A. Life-threatening hyperkalemia in an elderly patient receiving captopril, furosemide (frusemide) and potassium supplements. Drug. Saf. 1992; 7: 159-161.
  98. Wieland Т., Staubli M. Severe complications during enalapril therapy for heart insufficiency. Schweiz. Med. Wschr. 1988; 118: 1789-1792.
  99. Funck-Brentano C., Chatellier G., Alexandre J. M. Reversible renal failure after combined treatment with enalapril and frusemide in a patient with congestive heart failure. Br. Heart J. 1986; 55: 596-598.
  100. Cleland J. С., Dargie H. I., Pettigrew A. et al. The effects of captopril on serum digoxin and urinary urea and digoxin clearances in patients with congestive heart failure. Am. Heart J. 1986; 112: 130-135.
  101. van der Ent M., Remme W. J., de Leeuw P. W., Bartels G. L. Renal hemodynamic effects in patients with moderate to severe heart failure during chronic treatment with trandolapril. Cardiovasc. Drugs Ther. 1998; 12: 395-403.
  102. Cosin J., Diez J. Torasemide in chronic heart failure: results of the TOR1C study. Eur. J. Heart Failure 2002; 4: 507-513.
  103. Howard P. A., Dunn M. I. Severe heart failure in the elderly: potential benefits of high-dose and continuous infusion diuretics. Drugs & Aging 2002; 19: 249-256.
  104. Fans R., Flather M., Pureell H. et al. Current evidence supporting the role of diuretics in heart failure: a meta analysis of randomised controlled trials. Int. J. Cardiol. 2002: 82: 149- 158.
  105. Greenberg A. Diuretic complications. Am. J. Med. Sci. 2000; 319: 10-24.
  106. Waller P. C., Ramsay L. E. Predicting acute gout in diuretictreated hypertensive patients. J. Hum. Hypertens. 1989; 3: 457-461.'
  107. Spieker L. E., Ruschitzka F. Т., Luscher T. F., Noll G. The management of hyperuricemia and gout in patients with heart failure. Eur. J. Heart Failure 2002; 4: 403-410.
  108. Pitt W.J., Zannad F., Remme W.J. et al. The effect of spironolactone on morbidity and moratlity in patients with severe heart failure. Randomized Aldactone Evaluation Study.N. Engl. i. Med. 1999; 341: 709-717.
  109. Ни Y., Carpenter J. P., Cheung A. T. Life-threatening hyperkalemia: a complication of spironolactone for heart failure in a patient with renal insufficiency. Anesth. Analg. 2002; 95: 39- 41.
  110. Roy L. F., Villeneuve J. P., Dumont A. et al. Irreversible renal failure associated with triamterene. Am. J. Nephrol. 1991; 11: 486-488.
  111. Kim Y.-G., Kim В., Kim M.-K. et al. Medullary nephrocalcinosis associated with long-term furosemide abuse in adults. Nephrol. Dial. Transplant. 2001; 16: 2303-2309.
  112. Naafs M. A., van der Hoek C., van Duin S. et al. Decreased renal clearance of digoxin in chronic congestive heart failure.Eur. J. Clin. Pharmacol. 1985; 28: 249-252.
  113. Blackshear J. L., Davidman M., Stil/man M. T. Identification of risk for renal insufficiency from nonsteroidal anti-inflammatory drugs. Arch. Intern. Med.1983; 143: 1130-1134.
  114. Whelton A. Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications. Am. J. Med. 1999; 106 (5B): 13S-24S.
  115. Clive D. M., Stoff J. S. Renal syndromes, associated with nonsteroidal antiinflammatory drugs. N. Engl. J. Med. 1984; 310: 563-572.
  116. Dzau V. J., Packer M., Lilly L. S. et al. Prostaglandins in severe congestive heart failure. Relation to activation of reninangiotensin system and hyponatremia. Ibid. 347-352.
  117. Page J., Henry D. Consumption of NSAIDs and the development of congestive heart failure in elderly patient's. Arch. Intern. Med. 2000; 160: 777-784.
  118. Heerdink E. R., Leufkens H. G., Herings R. M. et al. NSAIDs associated with increased risk in elderlv patients taking diuretics. Ibid. 1998; 158: 1108-1112.
  119. Weinberg M. S., Quigg R. J., Salant D. J., Bernard D. B. Anuric renal failure precipitated by indomethacin and triamterene. Nephron 1985; 40:216-218.
  120. Perazella M. A., Eras J. Are selective COX-2 inhibitors nephrotoxic? Am. J. Kidney Dis. 2000; 129: 1423-1430.
  121. Teo K. K., Yusuf S., Pfeffer M. et al. Effects of long-term treatment with angiotensin-converting-enzyme inhibitors in the presence or absence of aspirin: a systematic review. Lancet 2002; 360: 1037-1043.

补充文件

附件文件
动作
1. JATS XML

版权所有 © Consilium Medicum, 2003

Creative Commons License
此作品已接受知识共享署名-非商业性使用-相同方式共享 4.0国际许可协议的许可。
 

Address of the Editorial Office:

  • Alabyan Street, 13/1, Moscow, 127055, Russian Federation

Correspondence address:

  • Alabyan Street, 13/1, Moscow, 127055, Russian Federation

Managing Editor:

  • Tel.: +7 (926) 905-41-26
  • E-mail: e.gorbacheva@ter-arkhiv.ru

 

© 2018-2021 "Consilium Medicum" Publishing house


##common.cookie##