(Circulation. 2001;103:1428.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Heart Rate and Cardiac Rhythm Relationships With Bisoprolol Benefit in Chronic Heart Failure in CIBIS II Trial
From the Pharmacology Department (P.L., J.-S.H.) and INSERM, Biostatistics and Mathematical Modeling Unit (S.E., A.M.), Pitié Salpêtrière Hospital, Paris; Clinical Pharmacology Unit, Lyon Hospitals (A.L.); Merck-Lipha, Clinical Research Department, Suresnes (M.W.-G.); and Hôpital Léon Binet, Provins (G.P.), France; and Clinical Research, University of Glasgow, UK (H.D.).
Correspondence to Prof Philippe Lechat, Service de Pharmacologie, Hôpital Pitié-Salpêtrière, 47 Boulevard de l’hôpital, 75013 Paris, France. E-mail philippe.lechat{at}psl.ap-hop-paris.fr
Background—ß-Blockade–induced benefit in heart failure (HF) could be related to baseline heart rate and treatment-induced heart rate reduction, but no such relationships have been demonstrated.
Methods and Results—In CIBIS II, we studied the relationships between baseline heart rate (BHR), heart rate changes at 2 months (HRC), nature of cardiac rhythm (sinus rhythm or atrial fibrillation), and outcomes (mortality and hospitalization for HF). Multivariate analysis of CIBIS II showed that in addition to ß-blocker treatment, BHR and HRC were both significantly related to survival and hospitalization for worsening HF, the lowest BHR and the greatest HRC being associated with best survival and reduction of hospital admissions. No interaction between the 3 variables was observed, meaning that on one hand, HRC-related improvement in survival was similar at all levels of BHR, and on the other hand, bisoprolol-induced benefit over placebo for survival was observed to a similar extent at any level of both BHR and HRC. Bisoprolol reduced mortality in patients with sinus rhythm (relative risk 0.58, P<0.001) but not in patients with atrial fibrillation (relative risk 1.16, P=NS). A similar result was observed for cardiovascular mortality and hospitalization for HF worsening.
Conclusions—BHR and HRC are significantly related to prognosis in heart failure. ß-Blockade with bisoprolol further improves survival at any level of BHR and HRC and to a similar extent. The benefit of bisoprolol is questionable, however, in patients with atrial fibrillation.
Key Words: heart failure • bisoprolol • receptors, adrenergic, beta • fibrillation • heart rate
This article has been cited by other articles:
 |
|
 |
|
  N. M. Hawkins, M. R. MacDonald, M. C. Petrie, G. W. Chalmers, R. Carter, F. G. Dunn, and J. J.V. McMurray Bisoprolol in patients with heart failure and moderate to severe chronic obstructive pulmonary disease: a randomized controlled trial Eur J Heart Fail, July 1, 2009; 11(7): 684 - 690. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. A. McAlister, N. Wiebe, J. A. Ezekowitz, A. A. Leung, and P. W. Armstrong Meta-analysis: {beta}-Blocker Dose, Heart Rate Reduction, and Death in Patients With Heart Failure Ann Intern Med, June 2, 2009; 150(11): 784 - 794. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Bohm, M. Thoenes, H.-R. Neuberger, S. Graber, J.-C. Reil, P. Bramlage, and M. Volpe Atrial fibrillation and heart rate independently correlate to microalbuminuria in hypertensive patients Eur. Heart J., June 1, 2009; 30(11): 1364 - 1371. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-C. Tardif Heart rate as a treatable cardiovascular risk factor Br. Med. Bull., June 1, 2009; 90(1): 71 - 84. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R J Shelton, A L Clark, K Goode, A S Rigby, T Houghton, G C Kaye, and J G F Cleland A randomised, controlled study of rate versus rhythm control in patients with chronic atrial fibrillation and heart failure: (CAFE-II Study) Heart, June 1, 2009; 95(11): 924 - 930. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T Nikolaidou and K S Channer Chronic atrial fibrillation: a systematic review of medical heart rate control management Postgrad. Med. J., June 1, 2009; 85(1004): 303 - 312. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Maurer, J. D. Sackner-Bernstein, L. El-Khoury Rumbarger, M. Yushak, D. L. King, and D. Burkhoff Mechanisms Underlying Improvements in Ejection Fraction With Carvedilol in Heart Failure Circ Heart Fail, May 1, 2009; 2(3): 189 - 196. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. G.F. Cleland and D. Cullington Digoxin: Quo Vadis? Circ Heart Fail, March 1, 2009; 2(2): 81 - 85. [Full Text] [PDF]
|
|
|
|
 |
|
 J. F. Doyle and K. M. Ho Benefits and Risks of Long-term Amiodarone Therapy for Persistent Atrial Fibrillation: A Meta-analysis Mayo Clin. Proc., March 1, 2009; 84(3): 234 - 242. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Logeart, J.-P. Gueffet, F. Rouzet, F. Pousset, C. Chavelas, A. C. Solal, and G. Jondeau Heart rate per se impacts cardiac function in patients with systolic heart failure and pacing: a pilot study Eur J Heart Fail, January 1, 2009; 11(1): 53 - 57. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Arya, M. Block, J. Kautzner, T. Lewalter, H. Mortel, S. Sack, B. Schumacher, P. Sogaard, M. Taborsky, D. Husser, et al. Influence of Home Monitoring on the clinical status of heart failure patients: Design and rationale of the IN-TIME study Eur J Heart Fail, November 1, 2008; 10(11): 1143 - 1148. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Nagele, W. Rodiger, and M. A. Castel Rate-responsive pacing in patients with heart failure: long-term results of a randomized study Europace, October 1, 2008; 10(10): 1182 - 1188. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Braunschweig, I. Ford, V. Conraads, M. R. Cowie, G. Jondeau, J. Kautzner, M. Lunati, R. M. Aguilera, C. M. Yu, M. Marijianowski, et al. Can monitoring of intrathoracic impedance reduce morbidity and mortality in patients with chronic heart failure? Rationale and design of the Diagnostic Outcome Trial in Heart Failure (DOT-HF) Eur J Heart Fail, September 1, 2008; 10(9): 907 - 916. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Borer Heart rate: from risk marker to risk factor Eur. Heart J. Suppl., August 1, 2008; 10(suppl_F): F2 - F6. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Ferrari, C. Ceconi, and G. Guardigli Pathophysiological role of heart rate: from ischaemia to left ventricular dysfunction Eur. Heart J. Suppl., August 1, 2008; 10(suppl_F): F7 - F10. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. M. De Ferrari, A. Mazzuero, L. Agnesina, A. Bertoletti, M. Lettino, C. Campana, P. J. Schwartz, and L. Tavazzi Favourable effects of heart rate reduction with intravenous administration of ivabradine in patients with advanced heart failure Eur J Heart Fail, June 1, 2008; 10(6): 550 - 555. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A S Hall and S Palmer The heart rate hypothesis: ready to be tested Heart, May 1, 2008; 94(5): 561 - 565. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nishio, Y. Sakata, T. Mano, T. Ohtani, Y. Takeda, T. Miwa, M. Hori, T. Masuyama, T. Kondo, and K. Yamamoto Beneficial effects of bisoprolol on the survival of hypertensive diastolic heart failure model rats Eur J Heart Fail, May 1, 2008; 10(5): 446 - 453. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Ciobotaru, M. Heimburger, L. Louedec, C. Heymes, R. Ventura-Clapier, P. Bedossa, B. Escoubet, J.-B. Michel, J.-J. Mercadier, and D. Logeart Effect of Long-Term Heart Rate Reduction by If Current Inhibition on Pressure Overload-Induced Heart Failure in Rats J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 43 - 49. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-R. Neuberger, C. Mewis, D. J. van Veldhuisen, U. Schotten, I. C. van Gelder, M. A. Allessie, and M. Bohm Management of atrial fibrillation in patients with heart failure Eur. Heart J., November 1, 2007; 28(21): 2568 - 2577. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Dobre, D. J. van Veldhuisen, M. J.L. deJongste, and F. M. Haaijer-Ruskamp Prescription of beta-blockers in patients with advanced heart failure and preserved left ventricular ejection fraction. Clinical implications and survival Eur J Heart Fail, September 1, 2007; 9(9): 962 - 963. [Full Text] [PDF]
|
|
|
|
|
|
A. Hjalmarson Heart rate: an independent risk factor in cardiovascular disease Eur. Heart J. Suppl., September 1, 2007; 9(suppl_F): F3 - F7. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. G. Steg Overview of large morbidity/mortality trials with ivabradine: focus on the BEAUTIfUL study Eur. Heart J. Suppl., September 1, 2007; 9(suppl_F): F15 - F19. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Swedberg Pure heart rate reduction: further perspectives in heart failure Eur. Heart J. Suppl., September 1, 2007; 9(suppl_F): F20 - F24. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Fox, J. S. Borer, A. J. Camm, N. Danchin, R. Ferrari, J. L. Lopez Sendon, P. G. Steg, J.-C. Tardif, L. Tavazzi, M. Tendera, et al. Resting Heart Rate in Cardiovascular Disease J. Am. Coll. Cardiol., August 28, 2007; 50(9): 823 - 830. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W.W. Wong and K.-H. Mak Impact of Maze and Concomitant Mitral Valve Surgery on Clinical Outcomes Ann. Thorac. Surg., November 1, 2006; 82(5): 1938 - 1947. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Agostoni, M. Contini, A. Magini, A. Apostolo, G. Cattadori, M. Bussotti, F. Veglia, D. Andreini, and P. Palermo Carvedilol reduces exercise-induced hyperventilation: A benefit in normoxia and a problem with hypoxia Eur J Heart Fail, November 1, 2006; 8(7): 729 - 735. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. C. Van Gelder, D. G. Wyse, M. L. Chandler, H. A. Cooper, B. Olshansky, V. E. Hagens, H. J.G.M. Crijns, the RACE, and AFFIRM Investigators Does intensity of rate-control influence outcome in atrial fibrillation? An analysis of pooled data from the RACE and AFFIRM studies Europace, November 1, 2006; 8(11): 935 - 942. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Cook, M. Togni, M. C. Schaub, P. Wenaweser, and O. M. Hess High heart rate: a cardiovascular risk factor? Eur. Heart J., October 2, 2006; 27(20): 2387 - 2393. [Full Text] [PDF]
|
|
|
|
|
|
L. Kober, K. Swedberg, J. J.V. McMurray, M. A. Pfeffer, E. J. Velazquez, R. Diaz, A. P. Maggioni, V. Mareev, G. Opolski, F. Van de Werf, et al. Previously known and newly diagnosed atrial fibrillation: A major risk indicator after a myocardial infarction complicated by heart failure or left ventricular dysfunction Eur J Heart Fail, October 1, 2006; 8(6): 591 - 598. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Writing Committee Members, V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: full text: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society Europace, September 1, 2006; 8(9): 651 - 745. [Full Text] [PDF]
|
|
|
|
|
|
J.-C. Tardif and C. Berry From coronary artery disease to heart failure: potential benefits of ivabradine Eur. Heart J. Suppl., September 1, 2006; 8(suppl_D): D24 - D29. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, J. E. Lowe, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society J. Am. Coll. Cardiol., August 15, 2006; 48(4): e149 - e246. [Full Text] [PDF]
|
|
|
|
 |
|
 V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, J. E. Lowe, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society Circulation, August 15, 2006; 114(7): e257 - e354. [Full Text] [PDF]
|
|
|
|
|
|
D. J. van Veldhuisen, H. Aass, D. El Allaf, P. H.J.M. Dunselman, L. Gullestad, M. Halinen, J. Kjekshus, L. Ohlsson, H. Wedel, J. Wikstrand, et al. Presence and development of atrial fibrillation in chronic heart failure: Experiences from the MERIT-HF Study Eur J Heart Fail, August 1, 2006; 8(5): 539 - 546. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K K A Witte, J G F Cleland, and A L Clark Chronic heart failure, chronotropic incompetence, and the effects of {beta} blockade Heart, April 1, 2006; 92(4): 481 - 486. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Lainscak and I. Keber Patients' knowledge and beta blocker treatment improve prognosis of patients from a heart failure clinic Eur J Heart Fail, March 1, 2006; 8(2): 187 - 190. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Fantoni, S. Raffa, F. Regoli, F. Giraldi, M. T. La Rovere, J. Prentice, F. Pastori, S. Fratini, J. A. Salerno-Uriarte, H. U. Klein, et al. Cardiac Resynchronization Therapy Improves Heart Rate Profile and Heart Rate Variability of Patients With Moderate to Severe Heart Failure J. Am. Coll. Cardiol., November 15, 2005; 46(10): 1875 - 1882. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Metra, C. Torp-Pedersen, K. Swedberg, J. G.F. Cleland, A. Di Lenarda, M. Komajda, W. J. Remme, B. Lutiger, A. Scherhag, M. A. Lukas, et al. Influence of heart rate, blood pressure, and beta-blocker dose on outcome and the differences in outcome between carvedilol and metoprolol tartrate in patients with chronic heart failure: results from the COMET trial Eur. Heart J., November 1, 2005; 26(21): 2259 - 2268. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. V. Naccarelli Antiadrenergic Therapy in the Control of Atrial Fibrillation Journal of Cardiovascular Pharmacology and Therapeutics, October 1, 2005; 10(4_suppl): S33 - S43. [Abstract] [PDF]
|
|
|
|
|
|
P. R. Kowey A Review of Carvedilol Arrhythmia Data in Clinical Trials Journal of Cardiovascular Pharmacology and Therapeutics, October 1, 2005; 10(4_suppl): S59 - S68. [Abstract] [PDF]
|
|
|
|
|
|
K. Fox Future perspectives of If inhibition in various cardiac conditions Eur. Heart J. Suppl., September 1, 2005; 7(suppl_H): H33 - H36. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Swedberg, L. G. Olsson, A. Charlesworth, J. Cleland, P. Hanrath, M. Komajda, M. Metra, C. Torp-Pedersen, and P. Poole-Wilson Prognostic relevance of atrial fibrillation in patients with chronic heart failure on long-term treatment with beta-blockers: results from COMET Eur. Heart J., July 1, 2005; 26(13): 1303 - 1308. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Gullestad, J. Wikstrand, P. Deedwania, A. Hjalmarson, K. Egstrup, U. Elkayam, S. Gottlieb, A. Rashkow, H. Wedel, G. Bermann, et al. What resting heart rate should one aim for when treating patients with heart failure with a beta-blocker?: Experiences from the Metoprolol Controlled Release/Extended Release Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF) J. Am. Coll. Cardiol., January 18, 2005; 45(2): 252 - 259. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Nemoto, P. Razeghi, M. Ishiyama, G. De Freitas, H. Taegtmeyer, and B. A. Carabello PPAR-{gamma} agonist rosiglitazone ameliorates ventricular dysfunction in experimental chronic mitral regurgitation Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H77 - H82. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Okoshi, M. Nakayama, X. Yan, M. P. Okoshi, A. J.T. Schuldt, M. A. Marchionni, and B. H. Lorell Neuregulins Regulate Cardiac Parasympathetic Activity: Muscarinic Modulation of {beta}-Adrenergic Activity in Myocytes From Mice With Neuregulin-1 Gene Deletion Circulation, August 10, 2004; 110(6): 713 - 717. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Quader, P. M. McCarthy, A. M. Gillinov, J. M. Alster, D. M. Cosgrove III, B. W. Lytle, and E. H. Blackstone Does preoperative atrial fibrillation reduce survival after coronary artery bypass grafting? Ann. Thorac. Surg., May 1, 2004; 77(5): 1514 - 1524. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Mulder, S. Barbier, A. Chagraoui, V. Richard, J. P. Henry, F. Lallemand, S. Renet, G. Lerebours, F. Mahlberg-Gaudin, and C. Thuillez Long-Term Heart Rate Reduction Induced by the Selective If Current Inhibitor Ivabradine Improves Left Ventricular Function and Intrinsic Myocardial Structure in Congestive Heart Failure Circulation, April 6, 2004; 109(13): 1674 - 1679. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J Janse Electrophysiological changes in heart failure and their relationship to arrhythmogenesis Cardiovasc Res, February 1, 2004; 61(2): 208 - 217. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Li, C. Zheng, T. Sato, T. Kawada, M. Sugimachi, and K. Sunagawa Vagal Nerve Stimulation Markedly Improves Long-Term Survival After Chronic Heart Failure in Rats Circulation, January 6, 2004; 109(1): 120 - 124. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. de Groote, N. Helbecque, N. Lamblin, X. Hermant, P. Amouyel, C. Bauters, and J. Dallongeville Beta-adrenergic receptor blockade and the angiotensin-converting enzyme deletion polymorphism in patients with chronic heart failure Eur J Heart Fail, January 1, 2004; 6(1): 17 - 21. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. U. Khand, A. C. Rankin, W. Martin, J. Taylor, I. Gemmell, and J. G. F. Cleland Carvedilol alone or in combination with digoxin for the management of atrial fibrillation in patients with heart failure? J. Am. Coll. Cardiol., December 3, 2003; 42(11): 1944 - 1951. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Danchin If current inhibition with ivabradine: further perspectives Eur. Heart J. Suppl., September 1, 2003; 5(suppl_G): G52 - G56. [Abstract] [PDF]
|
|
|
|
|
|
G. C. Gronefeld and S. H. Hohnloser Heart Failure Complicated by Atrial Fibrillation: Mechanistic, Prognostic, and Therapeutic Implications Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2003; 8(2): 107 - 113. [Abstract] [PDF]
|
|
|
|
|
|
T. Simon, M. Mary-Krause, C. Funck-Brentano, Ph. Lechat, P. Jaillon, and on behalf of CIBIS II investigators Bisoprolol dose-response relationship in patients with congestive heart failure: a subgroup analysis in the cardiac insufficiency bisoprolol study (CIBIS II) Eur. Heart J., March 2, 2003; 24(6): 552 - 559. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. G.F. Cleland, J. Ghosh, N. K. Khan, S. Ghio, L. Tavazzi, and G. Kaye Multi-chamber pacing: a perfect solution for cardiac mechanical dyssynchrony? Eur. Heart J., March 1, 2003; 24(5): 384 - 390. [Full Text] [PDF]
|
|
|
|
|
|
R H Arnold, E Kotlyar, C Hayward, A M Keogh, and P S Macdonald Relation between heart rate, heart rhythm, and reverse left ventricular remodelling in response to carvedilol in patients with chronic heart failure: a single centre, observational study Heart, March 1, 2003; 89(3): 293 - 298. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Savelieva and A. John Camm Atrial fibrillation and heart failure: natural history and pharmacological treatment Europace, January 1, 2003; 5(s1): S5 - S19. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W.H. Fung, S. K.W. Chan, L. Y.C. Yeung, and J. E. Sanderson Is beta-blockade useful in heart failure patients with atrial fibrillation? An analysis of data from two previously completed prospective trials Eur J Heart Fail, August 1, 2002; 4(4): 489 - 494. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Foody, M. H. Farrell, and H. M. Krumholz {beta}-Blocker Therapy in Heart Failure: Scientific Review JAMA, February 20, 2002; 287(7): 883 - 889. [Abstract] [Full Text] [PDF]
|
|