![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 284, Issue 2, 644-650, February 1998
Sanofi Recherche (M.R.C., F.B., J.M., J-M. D., P.C., C.C.,
D.O., M.S., M.B., M.P., J-C.B., G.L.F)
371 rue du Professeur Blayac,
34184 Montpellier Cedex 04 (France) and Sanofi Recherche (B.C., D.S),
Labège-Innopole voie1, BP137, 31676 Labège, Cédex 04 (France)
Based on both binding and functional data, this study introduces SR
144528 as the first, highly potent, selective and orally active
antagonist for the CB2 receptor. This compound which displays subnanomolar affinity (Ki = 0.6 nM) for both the
rat spleen and cloned human CB2 receptors has a 700-fold lower affinity
(Ki = 400 nM) for both the rat brain and cloned
human CB1 receptors. Furthermore it shows no affinity for any of the
more than 70 receptors, ion channels or enzymes investigated
(IC50 > 10 µM). In vitro, SR 144528 antagonizes the inhibitory effects of the cannabinoid receptor agonist
CP 55,940 on forskolin-stimulated adenylyl cyclase activity in cell
lines permanently expressing the h CB2 receptor (EC50 = 10 nM) but not in cells expressing the h CB1 (no effect at 10 µM).
Furthermore, SR 144528 is able to selectively block the
mitogen-activated protein kinase activity induced by CP 55,940 in cell
lines expressing h CB2 (IC50 = 39 nM) whereas in cells expressing h CB1 an IC50 value of more than 1 µM is
found. In addition, SR 144528 is shown to antagonize the stimulating
effects of CP 55,940 on human tonsillar B-cell activation evoked by
cross-linking of surface Igs (IC50 = 20 nM). In
vivo, after oral administration SR 144528 totally displaced the
ex vivo [3H]-CP 55,940 binding to mouse spleen
membranes (ED50 = 0.35 mg/kg) with a long duration of
action. In contrast, after the oral route it does not interact with the
cannabinoid receptor expressed in the mouse brain (CB1). It is expected
that SR 144528 will provide a powerful tool to investigate the in
vivo functions of the cannabinoid system in the immune response.
This article has been cited by other articles:
|
|
 |
|
  Y. F. Njie, Z. Qiao, Z. Xiao, W. Wang, and Z.-H. Song N-arachidonylethanolamide-Induced Increase in Aqueous Humor Outflow Facility Invest. Ophthalmol. Vis. Sci., October 1, 2008; 49(10): 4528 - 4534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Waldeck-Weiermair, C. Zoratti, K. Osibow, N. Balenga, E. Goessnitzer, M. Waldhoer, R. Malli, and W. F. Graier Integrin clustering enables anandamide-induced Ca2+ signaling in endothelial cells via GPR55 by protection against CB1-receptor-triggered repression J. Cell Sci., May 15, 2008; 121(10): 1704 - 1717. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Montecucco, F. Burger, F. Mach, and S. Steffens CB2 cannabinoid receptor agonist JWH-015 modulates human monocyte migration through defined intracellular signaling pathways Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1145 - H1155. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Esposito, T. Iuvone, C. Savani, C. Scuderi, D. De Filippis, M. Papa, V. Di Marzo, and L. Steardo Opposing Control of Cannabinoid Receptor Stimulation on Amyloid-beta-Induced Reactive Gliosis: In Vitro and in Vivo Evidence J. Pharmacol. Exp. Ther., September 1, 2007; 322(3): 1144 - 1152. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Benamar, M. Yondorf, J. J. Meissler, E. B. Geller, R. J. Tallarida, T. K. Eisenstein, and M. W. Adler A Novel Role of Cannabinoids: Implication in the Fever Induced by Bacterial Lipopolysaccharide J. Pharmacol. Exp. Ther., March 1, 2007; 320(3): 1127 - 1133. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Eggan and D. A. Lewis Immunocytochemical Distribution of the Cannabinoid CB1 Receptor in the Primate Neocortex: A Regional and Laminar Analysis Cereb Cortex, January 1, 2007; 17(1): 175 - 191. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. R. McMahon Characterization of Cannabinoid Agonists and Apparent pA2 Analysis of Cannabinoid Antagonists in Rhesus Monkeys Discriminating {Delta}9-Tetrahydrocannabinol J. Pharmacol. Exp. Ther., December 1, 2006; 319(3): 1211 - 1218. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Pacher, S. Batkai, and G. Kunos The Endocannabinoid System as an Emerging Target of Pharmacotherapy Pharmacol. Rev., September 1, 2006; 58(3): 389 - 462. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Wang, S. K. Dey, and M. Maccarrone Jekyll and Hyde: Two Faces of Cannabinoid Signaling in Male and Female Fertility Endocr. Rev., August 1, 2006; 27(5): 427 - 448. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Raduner, A. Majewska, J.-Z. Chen, X.-Q. Xie, J. Hamon, B. Faller, K.-H. Altmann, and J. Gertsch Alkylamides from Echinacea Are a New Class of Cannabinomimetics: CANNABINOID TYPE 2 RECEPTOR-DEPENDENT AND -INDEPENDENT IMMUNOMODULATORY EFFECTS J. Biol. Chem., May 19, 2006; 281(20): 14192 - 14206. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Lunn, J. S. Fine, A. Rojas-Triana, J. V. Jackson, X. Fan, T. T. Kung, W. Gonsiorek, M. A. Schwarz, B. Lavey, J. A. Kozlowski, et al. A Novel Cannabinoid Peripheral Cannabinoid Receptor-Selective Inverse Agonist Blocks Leukocyte Recruitment in Vivo J. Pharmacol. Exp. Ther., February 1, 2006; 316(2): 780 - 788. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. A. Cabral and F. Marciano-Cabral Cannabinoid receptors in microglia of the central nervous system: immune functional relevance J. Leukoc. Biol., December 1, 2005; 78(6): 1192 - 1197. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Kraft and H. G. Kress Indirect CB2 Receptor and Mediator-Dependent Stimulation of Human Whole-Blood Neutrophils by Exogenous and Endogenous Cannabinoids J. Pharmacol. Exp. Ther., November 1, 2005; 315(2): 641 - 647. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Zhong, L. Geng, Y. Njie, W. Feng, and Z.-H. Song CB2 Cannabinoid Receptors in Trabecular Meshwork Cells Mediate JWH015-Induced Enhancement of Aqueous Humor Outflow Facility Invest. Ophthalmol. Vis. Sci., June 1, 2005; 46(6): 1988 - 1992. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. G. Ramirez, C. Blazquez, T. G. del Pulgar, M. Guzman, and M. L. de Ceballos Prevention of Alzheimer's Disease Pathology by Cannabinoids: Neuroprotection Mediated by Blockade of Microglial Activation J. Neurosci., February 23, 2005; 25(8): 1904 - 1913. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. RODRIGUEZ de FONSECA, I. DEL ARCO, F. J. BERMUDEZ-SILVA, A. BILBAO, A. CIPPITELLI, and M. NAVARRO THE ENDOCANNABINOID SYSTEM: PHYSIOLOGY AND PHARMACOLOGY Alcohol Alcohol., January 1, 2005; 40(1): 2 - 14. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. G. Nackley, A. M. Zvonok, A. Makriyannis, and A. G. Hohmann Activation of Cannabinoid CB2 Receptors Suppresses C-Fiber Responses and Windup in Spinal Wide Dynamic Range Neurons in the Absence and Presence of Inflammation J Neurophysiol, December 1, 2004; 92(6): 3562 - 3574. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. H. Lichtman, D. Leung, C. C. Shelton, A. Saghatelian, C. Hardouin, D. L. Boger, and B. F. Cravatt Reversible Inhibitors of Fatty Acid Amide Hydrolase That Promote Analgesia: Evidence for an Unprecedented Combination of Potency and Selectivity J. Pharmacol. Exp. Ther., November 1, 2004; 311(2): 441 - 448. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Yoshihara, H. Morimoto, Y. Yamada, T. Abe, and O. Arisaka Cannabinoid Receptor Agonists Inhibit Sensory Nerve Activation in Guinea Pig Airways Am. J. Respir. Crit. Care Med., November 1, 2004; 170(9): 941 - 946. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J. Carrier, C. S. Kearn, A. J. Barkmeier, N. M. Breese, W. Yang, K. Nithipatikom, S. L. Pfister, W. B. Campbell, and C. J. Hillard Cultured Rat Microglial Cells Synthesize the Endocannabinoid 2-Arachidonylglycerol, Which Increases Proliferation via a CB2 Receptor-Dependent Mechanism Mol. Pharmacol., April 1, 2004; 65(4): 999 - 1007. [Abstract] [Full Text]
|
|
|
|
|
|
T. W. Klein, C. Newton, K. Larsen, L. Lu, I. Perkins, L. Nong, and H. Friedman The cannabinoid system and immune modulation J. Leukoc. Biol., October 1, 2003; 74(4): 486 - 496. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. L. F. Kaplan, C. E. Rockwell, and N. E. Kaminski Evidence for Cannabinoid Receptor-Dependent and -Independent Mechanisms of Action in Leukocytes J. Pharmacol. Exp. Ther., September 1, 2003; 306(3): 1077 - 1085. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Franklin, S. Parmentier-Batteur, L. Walter, D. A. Greenberg, and N. Stella Palmitoylethanolamide Increases after Focal Cerebral Ischemia and Potentiates Microglial Cell Motility J. Neurosci., August 27, 2003; 23(21): 7767 - 7775. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ruiu, G. A. Pinna, G. Marchese, J.-M. Mussinu, P. Saba, S. Tambaro, P. Casti, R. Vargiu, and L. Pani Synthesis and Characterization of NESS 0327: A Novel Putative Antagonist of the CB1 Cannabinoid Receptor J. Pharmacol. Exp. Ther., July 1, 2003; 306(1): 363 - 370. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Hilairet, M. Bouaboula, D. Carriere, G. Le Fur, and P. Casellas Hypersensitization of the Orexin 1 Receptor by the CB1 Receptor: EVIDENCE FOR CROSS-TALK BLOCKED BY THE SPECIFIC CB1 ANTAGONIST, SR141716 J. Biol. Chem., June 20, 2003; 278(26): 23731 - 23737. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Lee, F. L. Smith, D. L. Stevens, and S. P. Welch The Role of Several Kinases in Mice Tolerant to Delta 9-Tetrahydrocannabinol J. Pharmacol. Exp. Ther., May 1, 2003; 305(2): 593 - 599. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Tripathy, K. Kleppinger-Sparace, R. A. Dixon, and K. D. Chapman N-Acylethanolamine Signaling in Tobacco Is Mediated by a Membrane-Associated, High-Affinity Binding Protein Plant Physiology, April 1, 2003; 131(4): 1781 - 1791. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Walter, A. Franklin, A. Witting, C. Wade, Y. Xie, G. Kunos, K. Mackie, and N. Stella Nonpsychotropic Cannabinoid Receptors Regulate Microglial Cell Migration J. Neurosci., February 15, 2003; 23(4): 1398 - 1405. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Anikwue, J. W. Huffman, Z. L. Martin, and S. P. Welch Decrease in Efficacy and Potency of Nonsteroidal Anti-Inflammatory Drugs by Chronic Delta 9-Tetrahydrocannabinol Administration J. Pharmacol. Exp. Ther., October 1, 2002; 303(1): 340 - 346. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Joyeux, C. Arnaud, D. Godin-Ribuot, P. Demenge, D. Lamontagne, and C. Ribuot Endocannabinoids are implicated in the infarct size-reducing effect conferred by heat stress preconditioning in isolated rat hearts Cardiovasc Res, August 15, 2002; 55(3): 619 - 625. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Rawls, J. Cabassa, E. B. Geller, and M. W. Adler CB1 Receptors in the Preoptic Anterior Hypothalamus Regulate WIN 55212-2 [(4,5-Dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one]-Induced Hypothermia J. Pharmacol. Exp. Ther., June 1, 2002; 301(3): 963 - 968. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Howlett, F. Barth, T. I. Bonner, G. Cabral, P. Casellas, W. A. Devane, C. C. Felder, M. Herkenham, K. Mackie, B. R. Martin, et al. International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors Pharmacol. Rev., June 1, 2002; 54(2): 161 - 202. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T.-R. Jan, G. K. Rao, and N. E. Kaminski Cannabinol Enhancement of Interleukin-2 (IL-2) Expression by T Cells Is Associated with an Increase in IL-2 Distal Nuclear Factor of Activated T Cell Activity Mol. Pharmacol., February 1, 2002; 61(2): 446 - 454. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. D. Bukoski, S. Batkai, Z. Jarai, Y. Wang, L. Offertaler, W. F. Jackson, and G. Kunos CB1 Receptor Antagonist SR141716A Inhibits Ca2+-Induced Relaxation in CB1 Receptor-Deficient Mice Hypertension, February 1, 2002; 39(2): 251 - 257. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. O. P. Jacobsson, T. Wallin, and C. J. Fowler Inhibition of Rat C6 Glioma Cell Proliferation by Endogenous and Synthetic Cannabinoids. Relative Involvement of Cannabinoid and Vanilloid Receptors J. Pharmacol. Exp. Ther., December 1, 2001; 299(3): 951 - 959. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Sanchez, M. L. de Ceballos, T. G. del Pulgar, D. Rueda, C. Corbacho, G. Velasco, I. Galve-Roperh, J. W. Huffman, S. Ramon y Cajal, and M. Guzman Inhibition of Glioma Growth in Vivo by Selective Activation of the CB2 Cannabinoid Receptor Cancer Res., August 1, 2001; 61(15): 5784 - 5789. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Morisset and L. Urban Cannabinoid-Induced Presynaptic Inhibition of Glutamatergic EPSCs in Substantia Gelatinosa Neurons of the Rat Spinal Cord J Neurophysiol, July 1, 2001; 86(1): 40 - 48. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Iwamura, H. Suzuki, Y. Ueda, T. Kaya, and T. Inaba In Vitro and in Vivo Pharmacological Characterization of JTE-907, a Novel Selective Ligand for Cannabinoid CB2 Receptor J. Pharmacol. Exp. Ther., April 13, 2001; 296(2): 420 - 425. [Abstract] [Full Text]
|
|
|
|
 |
|
 T. W. Klein, B. Lane, C. A. Newton, and H. Friedman The Cannabinoid System and Cytokine Network Experimental Biology and Medicine, October 1, 2000; 225(1): 1 - 8. [Abstract] [Full Text]
|
|
|
|
 |
|
 L. X. Zhu, S. Sharma, M. Stolina, B. Gardner, M. D. Roth, D. P. Tashkin, and S. M. Dubinett {Delta}-9-Tetrahydrocannabinol Inhibits Antitumor Immunity by a CB2 Receptor-Mediated, Cytokine-Dependent Pathway J. Immunol., July 1, 2000; 165(1): 373 - 380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. W. Klein, C. A. Newton, N. Nakachi, and H. Friedman {Delta}9-Tetrahydrocannabinol Treatment Suppresses Immunity and Early IFN-{gamma}, IL-12, and IL-12 Receptor {beta}2 Responses to Legionella pneumophila Infection J. Immunol., June 15, 2000; 164(12): 6461 - 6466. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Chen and J. Buck Cannabinoids Protect Cells from Oxidative Cell Death: A Receptor-Independent Mechanism J. Pharmacol. Exp. Ther., June 1, 2000; 293(3): 807 - 812. [Abstract] [Full Text]
|
|
|
|
|
|
J.-M. Derocq, O. Jbilo, M. Bouaboula, M. Segui, C. Clere, and P. Casellas Genomic and Functional Changes Induced by the Activation of the Peripheral Cannabinoid Receptor CB2 in the Promyelocytic Cells HL-60. POSSIBLE INVOLVEMENT OF THE CB2 RECEPTOR IN CELL DIFFERENTIATION J. Biol. Chem., May 19, 2000; 275(21): 15621 - 15628. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Smith, C. Terminelli, and G. Denhardt Effects of Cannabinoid Receptor Agonist and Antagonist Ligands on Production of Inflammatory Cytokines and Anti-Inflammatory Interleukin-10 in Endotoxemic Mice J. Pharmacol. Exp. Ther., April 1, 2000; 293(1): 136 - 150. [Abstract] [Full Text]
|
|
|
|
|
|
G. Griffin, Q. Tao, and M. E. Abood Cloning and Pharmacological Characterization of the Rat CB2 Cannabinoid Receptor J. Pharmacol. Exp. Ther., March 1, 2000; 292(3): 886 - 894. [Abstract] [Full Text]
|
|
|
|
|
|
Z. Jarai, J. A. Wagner, S. K. Goparaju, L. Wang, R. K. Razdan, T. Sugiura, A. M. Zimmer, T. I. Bonner, A. Zimmer, and G. Kunos Cardiovascular Effects of 2-Arachidonoyl Glycerol in Anesthetized Mice Hypertension, February 1, 2000; 35(2): 679 - 684. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Sugiura, S. Kondo, S. Kishimoto, T. Miyashita, S. Nakane, T. Kodaka, Y. Suhara, H. Takayama, and K. Waku Evidence That 2-Arachidonoylglycerol but Not N-Palmitoylethanolamine or Anandamide Is the Physiological Ligand for the Cannabinoid CB2 Receptor. COMPARISON OF THE AGONISTIC ACTIVITIES OF VARIOUS CANNABINOID RECEPTOR LIGANDS IN HL-60 CELLS J. Biol. Chem., January 7, 2000; 275(1): 605 - 612. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Melck, L. De Petrocellis, P. Orlando, T. Bisogno, C. Laezza, M. Bifulco, and V. Di Marzo Suppression of Nerve Growth Factor Trk Receptors and Prolactin Receptors by Endocannabinoids Leads to Inhibition of Human Breast and Prostate Cancer Cell Proliferation Endocrinology, January 1, 2000; 141(1): 118 - 126. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-n. Chin, J. W. Murphy, J. W. Huffman, and D. A. Kendall The Third Transmembrane Helix of the Cannabinoid Receptor Plays a Role in the Selectivity of Aminoalkylindoles for CB2, Peripheral Cannabinoid Receptor J. Pharmacol. Exp. Ther., November 1, 1999; 291(2): 837 - 844. [Abstract] [Full Text]
|
|
|
|
|
|
M. Bouaboula, D. Dussossoy, and P. Casellas Regulation of Peripheral Cannabinoid Receptor CB2 Phosphorylation by the Inverse Agonist SR 144528. IMPLICATIONS FOR RECEPTOR BIOLOGICAL RESPONSES J. Biol. Chem., July 16, 1999; 274(29): 20397 - 20405. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Hillard, S. Manna, M. J. Greenberg, R. DiCamelli, R. A. Ross, L. A. Stevenson, V. Murphy, R. G. Pertwee, and W. B. Campbell Synthesis and Characterization of Potent and Selective Agonists of the Neuronal Cannabinoid Receptor (CB1) J. Pharmacol. Exp. Ther., June 1, 1999; 289(3): 1427 - 1433. [Abstract] [Full Text]
|
|
|
|
|
|
K. L. McCoy, M. Matveyeva, S. J. Carlisle, and G. A. Cabral Cannabinoid Inhibition of the Processing of Intact Lysozyme by Macrophages: Evidence for CB2 Receptor Participation J. Pharmacol. Exp. Ther., June 1, 1999; 289(3): 1620 - 1625. [Abstract] [Full Text]
|
|
|
|
|
|
T. Nagayama, A. D. Sinor, R. P. Simon, J. Chen, S. H. Graham, K. Jin, and D. A. Greenberg Cannabinoids and Neuroprotection in Global and Focal Cerebral Ischemia and in Neuronal Cultures J. Neurosci., April 15, 1999; 19(8): 2987 - 2995. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Bouaboula, N. Desnoyer, P. Carayon, T. Combes, and P. Casellas Gi Protein Modulation Induced by a Selective Inverse Agonist for the Peripheral Cannabinoid Receptor CB2: Implication for Intracellular Signalization Cross-Regulation. Mol. Pharmacol., March 1, 1999; 55(3): 473 - 480. [Abstract] [Full Text]
|
|
|
|
|
|
M. Portier, M. Rinaldi-Carmona, F. Pecceu, T. Combes, C. Poinot-Chazel, B. Calandra, F. Barth, G. L. Fur, and P. Casellas SR 144528, an Antagonist for the Peripheral Cannabinoid Receptor that Behaves as an Inverse Agonist J. Pharmacol. Exp. Ther., February 1, 1999; 288(2): 582 - 589. [Abstract] [Full Text]
|
|
|
|
 |
|
 K. Varga, J. A. Wagner, D. T. Bridgen, and G. Kunos Platelet- and macrophage-derived endogenous cannabinoids are involved in endotoxin-induced hypotension FASEB J, August 1, 1998; 12(11): 1035 - 1044. [Abstract] [Full Text]
|
|
 |
 |
 |
|
 |
 |
 |
