muscarinic agonists


Summary: Drugs that bind to and activate muscarinic cholinergic receptors (RECEPTORS, MUSCARINIC). Muscarinic agonists are most commonly used when it is desirable to increase smooth muscle tone, especially in the GI tract, urinary bladder and the eye. They may also be used to reduce heart rate.

Top Publications

  1. Bischoff V, Deogracias R, Poirier F, Barde Y. Seizure-induced neuronal death is suppressed in the absence of the endogenous lectin Galectin-1. J Neurosci. 2012;32:15590-600 pubmed publisher
    ..These findings provide new insights into the roles and regulation of endogenous lectins in the adult CNS and a surprisingly selective proapoptotic role of Gal-1 for a subpopulation of GABAergic interneurons. ..
  2. Buckmaster P, Ingram E, Wen X. Inhibition of the mammalian target of rapamycin signaling pathway suppresses dentate granule cell axon sprouting in a rodent model of temporal lobe epilepsy. J Neurosci. 2009;29:8259-69 pubmed publisher
    ..However, suppression required continual treatment, and rapamycin treatment did not reverse already established axon reorganization. ..
  3. Portelli J, Thielemans L, Ver Donck L, Loyens E, Coppens J, Aourz N, et al. Inactivation of the constitutively active ghrelin receptor attenuates limbic seizure activity in rodents. Neurotherapeutics. 2012;9:658-72 pubmed publisher
    ..This constitutes a novel mechanism of anticonvulsant action, whereby an endogenous agonist reduces the activity of a constitutively active receptor. ..
  4. Buchanan K, Petrovic M, Chamberlain S, Marrion N, Mellor J. Facilitation of long-term potentiation by muscarinic M(1) receptors is mediated by inhibition of SK channels. Neuron. 2010;68:948-63 pubmed publisher
    ..Thus, we describe a mechanism where M(1) receptor activation inhibits SK channels, allowing enhanced NMDAR activity and leading to a facilitation of LTP induction in the hippocampus. ..
  5. Belo A, Cheng K, Chahdi A, Shant J, Xie G, Khurana S, et al. Muscarinic receptor agonists stimulate human colon cancer cell migration and invasion. Am J Physiol Gastrointest Liver Physiol. 2011;300:G749-60 pubmed publisher
    ..In concert with previous observations, these findings indicate that muscarinic receptor signaling plays a key role in colon cancer cell proliferation, survival, migration, and invasion. ..
  6. Pak K, Ostrom R, Matsui M, Ehlert F. Impaired M3 and enhanced M2 muscarinic receptor contractile function in a streptozotocin model of mouse diabetic urinary bladder. Naunyn Schmiedebergs Arch Pharmacol. 2010;381:441-54 pubmed publisher
    ..M2 receptor activation opposes forskolin-induced relaxation of the urinary bladder, and this M(2) function is enhanced following streptozotocin treatment. ..
  7. Davis C, Bradley S, Schiffer H, Friberg M, Koch K, Tolf B, et al. Differential regulation of muscarinic M1 receptors by orthosteric and allosteric ligands. BMC Pharmacol. 2009;9:14 pubmed publisher
    ..Thus, signaling and regulatory pathways induced by different allosteric ligands are ligand specific. ..
  8. Uray F, de Alfonzo R, de Becemberg I, Alfonzo M. Muscarinic agonists acting through M2 acetylcholine receptors stimulate the migration of an NO-sensitive guanylyl cyclase to the plasma membrane of bovine tracheal smooth muscle. J Recept Signal Transduct Res. 2010;30:10-23 pubmed publisher
    b>Muscarinic agonists acting on bovine tracheal smooth muscle (BTSM) induce two separate cGMP signals, one at 20 sec associated with NO-sensitive-soluble-guanylyl-cyclase (NO-sGC) and another at 60 sec, linked to natriuretic-peptide-GC...
  9. Kuzmenkin A, Liang H, Xu G, Pfannkuche K, Eichhorn H, Fatima A, et al. Functional characterization of cardiomyocytes derived from murine induced pluripotent stem cells in vitro. FASEB J. 2009;23:4168-80 pubmed publisher
    ..This difference may reflect the incomplete reprogramming of iPS cells and should be critically considered in further studies to clarify the suitability of the iPS model for regenerative medicine of heart disorders. ..

More Information


  1. Ziegler N, Bätz J, Zabel U, Lohse M, Hoffmann C. FRET-based sensors for the human M1-, M3-, and M5-acetylcholine receptors. Bioorg Med Chem. 2011;19:1048-54 pubmed publisher
    ..Taken together our data support the notion that orthosteric agonists behave similar at different muscarinic receptor subtypes but that kinetic differences can be observed for receptor activation. ..
  2. Al Izki S, Pryce G, Giovannoni G, Baker D. Evaluating potential therapies for bladder dysfunction in a mouse model of multiple sclerosis with high-resolution ultrasonography. Mult Scler. 2009;15:795-801 pubmed publisher
    ..Such signs can develop in animal models of MS. Current assessments of bladder properties in animal models are generally invasive, electrophysiological techniques...
  3. Raufman J, Cheng K, Saxena N, Chahdi A, Belo A, Khurana S, et al. Muscarinic receptor agonists stimulate matrix metalloproteinase 1-dependent invasion of human colon cancer cells. Biochem Biophys Res Commun. 2011;415:319-24 pubmed publisher
  4. Gonzalez J, Albiñana E, Baldelli P, Garcia A, Hernandez Guijo J. Presynaptic muscarinic receptor subtypes involved in the enhancement of spontaneous GABAergic postsynaptic currents in hippocampal neurons. Eur J Neurosci. 2011;33:69-81 pubmed publisher
  5. Suh B, Leal K, Hille B. Modulation of high-voltage activated Ca(2+) channels by membrane phosphatidylinositol 4,5-bisphosphate. Neuron. 2010;67:224-38 pubmed publisher
    ..Thus, endogenous membrane PIP(2) supports high-voltage activated L-, N-, and P/Q-type Ca(2+) channels, and stimuli that activate phospholipase C deplete PIP(2) and reduce those Ca(2+) channel currents. ..
  6. Griffin M, Matsui M, Ostrom R, Ehlert F. The guinea pig ileum lacks the direct, high-potency, M(2)-muscarinic, contractile mechanism characteristic of the mouse ileum. Naunyn Schmiedebergs Arch Pharmacol. 2009;380:327-35 pubmed publisher
    ..The guinea pig ileum, therefore, lacks a direct, highly potent, M(2)-contractile component but may have a direct, lower potency M(2) component. ..
  7. Sellin A, Shad M, Tamminga C. Muscarinic agonists for the treatment of cognition in schizophrenia. CNS Spectr. 2008;13:985-96 pubmed
    ..We present an overview of likely side effects of muscarinic agonists. We outline the anticholinergic activity of several available antipsychotics and review the available M1 ..
  8. Carrillo Reid L, Tecuapetla F, Ibanez Sandoval O, Hernandez Cruz A, Galarraga E, Bargas J. Activation of the cholinergic system endows compositional properties to striatal cell assemblies. J Neurophysiol. 2009;101:737-49 pubmed publisher
    ..Neuronal recurrent networks with the characteristics encountered in the present experiments are proposed to allow repeated sequences of activity to become memories and repeated memories to compose learned motor procedures. ..
  9. Falenski K, Carter D, Harrison A, Martin B, Blair R, Delorenzo R. Temporal characterization of changes in hippocampal cannabinoid CB(1) receptor expression following pilocarpine-induced status epilepticus. Brain Res. 2009;1262:64-72 pubmed publisher
    ..This suggests a role for dysregulation of the endocannabinoid system during epileptogenesis and indicates that the CB(1) receptor redistribution temporally correlates with the emergence of epileptic seizures. ..
  10. Cui Q, Fogle E, Almazan G. Muscarinic acetylcholine receptors mediate oligodendrocyte progenitor survival through Src-like tyrosine kinases and PI3K/Akt pathways. Neurochem Int. 2006;48:383-93 pubmed
  11. Finney S, Stewart L, Gillespie J. Cholinergic activation of phasic activity in the isolated bladder: possible evidence for M3- and M2-dependent components of a motor/sensory system. BJU Int. 2007;100:668-78 pubmed
    To analyse pressure changes induced by muscarinic agonists on the isolated bladder in order to examine whether there are different responses representing different components of a motor/sensory system within the bladder wall...
  12. Tran J, Matsui M, Ehlert F. Differential coupling of muscarinic M1, M2, and M3 receptors to phosphoinositide hydrolysis in urinary bladder and longitudinal muscle of the ileum of the mouse. J Pharmacol Exp Ther. 2006;318:649-56 pubmed
    ..These data suggest a major role for the M3 receptor in eliciting phosphoinositide hydrolysis in the ileum and urinary bladder and minor roles for the M1 and M2 in ileum. ..
  13. Zuberi Z, Birnbaumer L, Tinker A. The role of inhibitory heterotrimeric G proteins in the control of in vivo heart rate dynamics. Am J Physiol Regul Integr Comp Physiol. 2008;295:R1822-30 pubmed publisher
    ..In contrast, Galphai1 and Galphai3 do not appear to be essential for parasympathetic responses in vivo. ..
  14. Ruggieri M, Braverman A. Regulation of bladder muscarinic receptor subtypes by experimental pathologies. Auton Autacoid Pharmacol. 2006;26:311-25 pubmed
    ..This finding has substantial implications for the clinical treatment of abnormal bladder contractions. ..
  15. Marchi N, Oby E, Batra A, Uva L, de Curtis M, Hernandez N, et al. In vivo and in vitro effects of pilocarpine: relevance to ictogenesis. Epilepsia. 2007;48:1934-46 pubmed
    ..g. K+) into the brain leading to pilocarpine-induced SE. Disturbance of brain homeostasis represents an etiological factor contributing to pilocarpine seizures. ..
  16. Fisher A. M1 muscarinic agonists target major hallmarks of Alzheimer's disease--the pivotal role of brain M1 receptors. Neurodegener Dis. 2008;5:237-40 pubmed publisher
    ..M1 muscarinic receptor (M1 mAChR) is a therapeutic target in Alzheimer's disease (AD) and the M1-selective muscarinic agonists AF102B, AF150(S) and AF267B are cognitive enhancers and potential disease modifiers...
  17. Brown D, Passmore G. Neural KCNQ (Kv7) channels. Br J Pharmacol. 2009;156:1185-95 pubmed publisher
    ..Flupirtine is in use as a central analgesic; retigabine is under clinical trial as a broad-spectrum anticonvulsant and is an effective analgesic in animal models of chronic inflammatory and neuropathic pain. ..
  18. Buhl E, Schildberger K, Stevenson P. A muscarinic cholinergic mechanism underlies activation of the central pattern generator for locust flight. J Exp Biol. 2008;211:2346-57 pubmed publisher
  19. Jakubik J, Michal P, Machová E, Dolezal V. Importance and prospects for design of selective muscarinic agonists. Physiol Res. 2008;57 Suppl 3:S39-47 pubmed
    ..The selectivity of classical muscarinic agonists among receptor subtypes is very low due to the highly conserved nature of the orthosteric binding site ..
  20. Goffin K, Nissinen J, Van Laere K, Pitkanen A. Cyclicity of spontaneous recurrent seizures in pilocarpine model of temporal lobe epilepsy in rat. Exp Neurol. 2007;205:501-5 pubmed
    ..Finally, our data suggest that the model can be used for studies aiming at identifying the mechanisms of seizure clustering. ..
  21. Altar C, Hunt R, Jurata L, Webster M, Derby E, Gallagher P, et al. Insulin, IGF-1, and muscarinic agonists modulate schizophrenia-associated genes in human neuroblastoma cells. Biol Psychiatry. 2008;64:1077-87 pubmed publisher
    ..Most of 1940 pharmacologically unique compounds failed to alter gene expression, with the exception of muscarinic agonists, which mimicked insulin and IGF-1, and which were blocked by the muscarinic antagonists atropine and ..
  22. Shekhar A, Potter W, Lightfoot J, Lienemann J, Dube S, Mallinckrodt C, et al. Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. Am J Psychiatry. 2008;165:1033-9 pubmed publisher
    ..These results support further investigation of xanomeline as a novel approach to treating schizophrenia. ..
  23. Lopes Aguiar C, Romcy Pereira R, Escorsim Szawka R, Galvis Alonso O, Anselmo Franci J, Pereira Leite J. Muscarinic acetylcholine neurotransmission enhances the late-phase of long-term potentiation in the hippocampal-prefrontal cortex pathway of rats in vivo: a possible involvement of monoaminergic systems. Neuroscience. 2008;153:1309-19 pubmed publisher
    ..Our data, therefore, suggest that muscarinic activation exerts a boosting effect on mPFC synaptic plasticity and possibly on mPFC-dependent memories, associated to monoaminergic changes. ..
  24. Spalding T, Ma J, Ott T, Friberg M, Bajpai A, Bradley S, et al. Structural requirements of transmembrane domain 3 for activation by the M1 muscarinic receptor agonists AC-42, AC-260584, clozapine, and N-desmethylclozapine: evidence for three distinct modes of receptor activation. Mol Pharmacol. 2006;70:1974-83 pubmed
    ..crucial role mediating muscarinic acetylcholine receptor activation by acetylcholine, carbachol, and other muscarinic agonists. We compared the effects of point mutations throughout TM3 on the interactions of carbachol, 4-n-butyl-1-[4-..
  25. Uva L, Librizzi L, Marchi N, Noe F, Bongiovanni R, Vezzani A, et al. Acute induction of epileptiform discharges by pilocarpine in the in vitro isolated guinea-pig brain requires enhancement of blood-brain barrier permeability. Neuroscience. 2008;151:303-12 pubmed
    ..Pilocarpine accumulation secondary to BBB permeability changes may contribute to in vivo ictogenesis in the pilocarpine epilepsy model. ..
  26. Langmead C, Watson J, Reavill C. Muscarinic acetylcholine receptors as CNS drug targets. Pharmacol Ther. 2008;117:232-43 pubmed
  27. Conn P, Jones C, Lindsley C. Subtype-selective allosteric modulators of muscarinic receptors for the treatment of CNS disorders. Trends Pharmacol Sci. 2009;30:148-55 pubmed publisher
  28. Marlo J, Niswender C, Days E, Bridges T, Xiang Y, Rodriguez A, et al. Discovery and characterization of novel allosteric potentiators of M1 muscarinic receptors reveals multiple modes of activity. Mol Pharmacol. 2009;75:577-88 pubmed publisher
    ..These data also suggest that structurally diverse M(1) potentiators may act by distinct mechanisms and differentially regulate receptor coupling to downstream signaling pathways. ..
  29. Stevens L, Sellers D, McKay N, Chapple C, Chess Williams R. Muscarinic receptor function, density and G-protein coupling in the overactive diabetic rat bladder. Auton Autacoid Pharmacol. 2006;26:303-9 pubmed
    1 Bladder smooth muscle sensitivity to muscarinic agonists is increased in the overactive bladder...
  30. De Lorme K, Grant M, Noetzel M, Polson S, El Fakahany E. Long-term changes in the muscarinic M1 receptor induced by instantaneous formation of wash-resistant xanomeline-receptor complex. J Pharmacol Exp Ther. 2007;323:868-76 pubmed
    ..Our results imply that brief exposure to xanomeline followed by washing and prolonged waiting may result in delayed receptor desensitization accompanied by internalization or down-regulation...
  31. Ehlert F, Ahn S, Pak K, Park G, Sangnil M, Tran J, et al. Neuronally released acetylcholine acts on the M2 muscarinic receptor to oppose the relaxant effect of isoproterenol on cholinergic contractions in mouse urinary bladder. J Pharmacol Exp Ther. 2007;322:631-7 pubmed
  32. Langmead C, Austin N, Branch C, Brown J, Buchanan K, Davies C, et al. Characterization of a CNS penetrant, selective M1 muscarinic receptor agonist, 77-LH-28-1. Br J Pharmacol. 2008;154:1104-15 pubmed publisher
    ..These data suggest that 77-LH-28-1 is a potent, selective, bioavailable and brain-penetrant agonist at the M1 mAChR and therefore that it represents a better tool than AC-42, with which to study the pharmacology of the M1 mAChR. ..
  33. Bolter C, English D. The effects of tertiapin-Q on responses of the sinoatrial pacemaker of the guinea-pig heart to vagal nerve stimulation and muscarinic agonists. Exp Physiol. 2008;93:53-63 pubmed
    ..IK,ACh, in the bradycardia produced by electrical stimulation of the vagus (parasympathetic) nerve and muscarinic agonists (ACh and bethanecol, bolus i.a.)...
  34. Thomas R, Mistry R, Langmead C, Wood M, Challiss R. G protein coupling and signaling pathway activation by m1 muscarinic acetylcholine receptor orthosteric and allosteric agonists. J Pharmacol Exp Ther. 2008;327:365-74 pubmed publisher
    ..77-LH-28-1 (1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone), and a range of orthosteric muscarinic agonists [oxotremorine-M (oxo-M), arecoline, and pilocarpine] in Chinese hamster ovary cells recombinantly ..
  35. Burlage F, Faber H, Kampinga H, Langendijk J, Vissink A, Coppes R. Enhanced proliferation of acinar and progenitor cells by prophylactic pilocarpine treatment underlies the observed amelioration of radiation injury to parotid glands. Radiother Oncol. 2009;90:253-6 pubmed publisher
    ..Amelioration of early loss of rat salivary gland function after radiation by pilocarpine pre-treatment is, at least in part, due to compensatory mechanisms through increased proliferation of undamaged cells. ..
  36. Lin A, Zhu B, Zhang W, Dang H, Zhang B, Katz M, et al. Distinct pathways of ERK activation by the muscarinic agonists pilocarpine and carbachol in a human salivary cell line. Am J Physiol Cell Physiol. 2008;294:C1454-64 pubmed publisher
    ..We examined the activation of ERK1/2 by two muscarinic agonists, pilocarpine and carbachol, in a human salivary cell line (HSY)...
  37. De Lorme K, Sikorski K, Grant M, El Fakahany E. Long-term wash-resistant effects of brief interaction of xanomeline at the M1 muscarinic receptor. Neurosci Lett. 2006;410:11-4 pubmed
    ..However, possible involvement of other mechanisms of long-term receptor regulation cannot be discounted. ..
  38. Ehlert F, Griffin M. Two-state models and the analysis of the allosteric effect of gallamine at the M2 muscarinic receptor. J Pharmacol Exp Ther. 2008;325:1039-60 pubmed publisher
    ..If it is assumed that allosterism occurs at the relay site and not the activation site, then this model can account for affinity-only modulation in a manner consistent with the allosteric ternary complex model. ..
  39. Fisher A. M1 muscarinic agonists target major hallmarks of Alzheimer's disease--an update. Curr Alzheimer Res. 2007;4:577-80 pubmed
    ..g. cholinergic deficiency, cognitive dysfunctions, beta-amyloid (Abeta) and tau pathologies. Some muscarinic agonists, while effective in AD, had limited clinical value due to adverse effects and lack of M1 selectivity...
  40. Gautam D, Han S, Hamdan F, Jeon J, Li B, Li J, et al. A critical role for beta cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo. Cell Metab. 2006;3:449-61 pubmed
    ..These findings indicate that beta cell M3 muscarinic receptors play a key role in maintaining proper insulin release and glucose homeostasis. ..
  41. Jakubik J, El Fakahany E, Dolezal V. Differences in kinetics of xanomeline binding and selectivity of activation of G proteins at M(1) and M(2) muscarinic acetylcholine receptors. Mol Pharmacol. 2006;70:656-66 pubmed
    ..These conformations are both time- and concentration-dependent and vary between the M(1) and the M(2) receptor. ..
  42. Wess J, Eglen R, Gautam D. Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development. Nat Rev Drug Discov. 2007;6:721-33 pubmed
    ..Importantly, these studies have identified specific mAChR-regulated pathways as potentially novel targets for the treatment of various important disorders including Alzheimer's disease, schizophrenia, pain, obesity and diabetes. ..
  43. Dowling M, Willets J, Budd D, Charlton S, Nahorski S, Challiss R. A single point mutation (N514Y) in the human M3 muscarinic acetylcholine receptor reveals differences in the properties of antagonists: evidence for differential inverse agonism. J Pharmacol Exp Ther. 2006;317:1134-42 pubmed
  44. Nsabimana A, Ojewole J. Diabetes mellitus and responses of the urinary bladder to acetylcholine: an in vitro study. J Smooth Muscle Res. 2008;44:143-50 pubmed
    ..on the responses of diabetic bladder strips to cholinergic nerve stimulation or exogenously-administered muscarinic agonists, especially acetylcholine (ACh)...
  45. Fisher A. Cholinergic treatments with emphasis on m1 muscarinic agonists as potential disease-modifying agents for Alzheimer's disease. Neurotherapeutics. 2008;5:433-42 pubmed publisher
    ..the advantages and drawbacks of some cholinergic compounds, such as acetylcholinesterase inhibitors, M1 muscarinic agonists, M2 antagonists, and nicotinic agonists...
  46. Fabene P, Merigo F, Galiè M, Benati D, Bernardi P, Farace P, et al. Pilocarpine-induced status epilepticus in rats involves ischemic and excitotoxic mechanisms. PLoS ONE. 2007;2:e1105 pubmed
    ..Both of these degenerative pathways, as well as the widespread and severe brain damage observed, should be considered when animal model-based data are compared to human pathology. ..
  47. Sakamoto T, Unno T, Kitazawa T, Taneike T, Yamada M, Wess J, et al. Three distinct muscarinic signalling pathways for cationic channel activation in mouse gut smooth muscle cells. J Physiol. 2007;582:41-61 pubmed
    ..The delineation of this pathway is consistent with the formation of a functional unit by the M2-Go protein and the M3-PLC systems predicted to control cationic channels. ..
  48. Hughes S, Marsh S, Tinker A, Brown D. PIP(2)-dependent inhibition of M-type (Kv7.2/7.3) potassium channels: direct on-line assessment of PIP(2) depletion by Gq-coupled receptors in single living neurons. Pflugers Arch. 2007;455:115-24 pubmed
  49. Falenski K, Blair R, Sim Selley L, Martin B, DeLorenzo R. Status epilepticus causes a long-lasting redistribution of hippocampal cannabinoid type 1 receptor expression and function in the rat pilocarpine model of acquired epilepsy. Neuroscience. 2007;146:1232-44 pubmed
  50. Kanai A, Roppolo J, Ikeda Y, Zabbarova I, Tai C, Birder L, et al. Origin of spontaneous activity in neonatal and adult rat bladders and its enhancement by stretch and muscarinic agonists. Am J Physiol Renal Physiol. 2007;292:F1065-72 pubmed
    ..the origin of spontaneous activity in neonatal and adult rat bladders and the effect of stretch and muscarinic agonists and antagonists on spontaneous activity...
  51. Covolan L, Mello L. Assessment of the progressive nature of cell damage in the pilocarpine model of epilepsy. Braz J Med Biol Res. 2006;39:915-24 pubmed
    ..As a consequence of both mechanisms, subsequent insults after an initial insult result in very little damage regardless of their intensity. ..
  52. Gregory K, Sexton P, Tobin A, Christopoulos A. Stimulus bias provides evidence for conformational constraints in the structure of a G protein-coupled receptor. J Biol Chem. 2012;287:37066-77 pubmed publisher
    ..Furthermore, we provide evidence that downstream signaling pathways previously considered to be related to each other (i.e. receptor phosphorylation, internalization, and activation of ERK1/2) can act independently. ..
  53. Tabira T. [Development of new drugs for Alzheimer's disease]. Brain Nerve. 2010;62:787-96 pubmed
    ..Some of these drugs are in phase III clinical trials and are expected to be available for clinical use in the near future. ..
  54. Arrighi N, Bodei S, Zani D, Simeone C, Cunico S, Spano P, et al. [Acetylcholine induces human detrusor muscle cell proliferation: molecular and pharmacological characterization]. Urologia. 2012;79:102-8 pubmed publisher
    ..These results could help to better understand the role of antimuscarinic drugs, which are currently used for the treatment of many urological diseases...
  55. Pronin A, Wang Q, Slepak V. Teaching an Old Drug New Tricks: Agonism, Antagonism, and Biased Signaling of Pilocarpine through M3 Muscarinic Acetylcholine Receptor. Mol Pharmacol. 2017;92:601-612 pubmed publisher
    ..We found that pilocarpine was 1000 times less potent in stimulating mouse-eye pupil constriction than muscarinic agonists oxotremorin-M (Oxo-M) or carbachol (CCh), although all three ligands have similar Kd ..