Famotidine inhibits toll-like receptor 3-mediated inflammatory signaling in SARS-CoV-2 infection

Abstract

Apart from prevention using vaccinations, the management options for COVID-19 remain limited. In retrospective cohort studies, use of famotidine, a specific oral H2 receptor antagonist (antihistamine), has been associated with reduced risk of intubation and death in patients hospitalized with COVID-19. In a case series, nonhospitalized patients with COVID-19 experienced rapid symptom resolution after taking famotidine, but the molecular basis of these observations remains elusive. Here we show using biochemical, cellular, and functional assays that famotidine has no effect on viral replication or viral protease activity. However, famotidine can affect histamine-induced signaling processes in infected Caco2 cells. Specifically, famotidine treatment inhibits histamine-induced expression of Toll-like receptor 3 (TLR3) in SARS-CoV-2 infected cells and can reduce TLR3-dependent signaling processes that culminate in activation of IRF3 and the NF-κB pathway, subsequently controlling antiviral and inflammatory responses. SARS-CoV-2-infected cells treated with famotidine demonstrate reduced expression levels of the inflammatory mediators CCL-2 and IL6, drivers of the cytokine release syndrome that precipitates poor outcome for patients with COVID-19. Given that pharmacokinetic studies indicate that famotidine can reach concentrations in blood that suffice to antagonize histamine H2 receptors expressed in mast cells, neutrophils, and eosinophils, these observations explain how famotidine may contribute to the reduced histamine-induced inflammation and cytokine release, thereby improving the outcome for patients with COVID-19. Apart from prevention using vaccinations, the management options for COVID-19 remain limited. In retrospective cohort studies, use of famotidine, a specific oral H2 receptor antagonist (antihistamine), has been associated with reduced risk of intubation and death in patients hospitalized with COVID-19. In a case series, nonhospitalized patients with COVID-19 experienced rapid symptom resolution after taking famotidine, but the molecular basis of these observations remains elusive. Here we show using biochemical, cellular, and functional assays that famotidine has no effect on viral replication or viral protease activity. However, famotidine can affect histamine-induced signaling processes in infected Caco2 cells. Specifically, famotidine treatment inhibits histamine-induced expression of Toll-like receptor 3 (TLR3) in SARS-CoV-2 infected cells and can reduce TLR3-dependent signaling processes that culminate in activation of IRF3 and the NF-κB pathway, subsequently controlling antiviral and inflammatory responses. SARS-CoV-2-infected cells treated with famotidine demonstrate reduced expression levels of the inflammatory mediators CCL-2 and IL6, drivers of the cytokine release syndrome that precipitates poor outcome for patients with COVID-19. Given that pharmacokinetic studies indicate that famotidine can reach concentrations in blood that suffice to antagonize histamine H2 receptors expressed in mast cells, neutrophils, and eosinophils, these observations explain how famotidine may contribute to the reduced histamine-induced inflammation and cytokine release, thereby improving the outcome for patients with COVID-19. The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) affected more than 100 million people with more than 2 million deaths as of February 18, 2021. Many drugs are being repurposed for COVID-19 therapy, often based on insufficient evidence from randomized trials. Famotidine is an approved drug for peptic ulcers and gastroesophageal reflux disease (GERD) (Fig. 1A). It acts as a competitive antagonist of histamine in gastric parietal cells. Histamine activates protein kinase A (PKA), which causes movement of H+/K+ transporters to the membrane resulting in more acid secretion. Famotidine counters this activity, thereby reducing acid secretion in GERD patients. Several independent case studies on COVID-19 patients have suggested the use of this H2-receptor antagonist in the treatment of disease. Famotidine reduces the risk of intubation and death in hospitalized COVID-19 patients (1Freedberg D.E. Conigliaro J. Wang T.C. Tracey K.J. Callahan M.V. Abrams J.A. Famotidine Research GroupFamotidine use is associated with improved clinical outcomes in hospitalized COVID-19 patients: A propensity score matched retrospective cohort study.Gastroenterology. 2020; 159: 1129-1131.e3Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar, 2Mather J.F. Seip R.L. McKay R.G. Impact of Famotidine use on clinical outcomes of hospitalized patients with COVID-19.Am. J. Gastroenterol. 2020; 115: 1617-1623Crossref PubMed Scopus (85) Google Scholar). It has also been suggested to reduce respiratory symptoms in nonhospitalized patients (3Janowitz T. Gablenz E. Pattinson D. Wang T.C. Conigliaro J. Tracey K. Tuveson D. Famotidine use and quantitative symptom tracking for COVID-19 in non-hospitalised patients: A case series.Gut. 2020; 69: 1592-1597Crossref PubMed Scopus (84) Google Scholar). In combination with the H1-receptor antagonist cetirizine, it has been shown to reduce pulmonary distress in hospitalized COVID-19 patients (4Hogan II, R.B. Hogan III, R.B. Cannon T. Rappai M. Studdard J. Paul D. Dooley T.P. Dual-histamine receptor blockade with cetirizine-famotidine reduces pulmonary symptoms in COVID-19 patients.Pulm. Pharmacol. Ther. 2020; 63: 101942Crossref PubMed Scopus (52) Google Scholar). These studies indicated that famotidine has a beneficial role in managing COVID-19 disease symptoms, but the molecular basis of these observations remained elusive. The SARS-CoV-2 main protease (CoV-2 3CLpro) and Papain-like protease (SARS-CoV-2 PLpro) have been suggested to be the targets of famotidine based on several virtual screening studies (5Wu C. Liu Y. Yang Y. Zhang P. Zhong W. Wang Y. Wang Q. Xu Y. Li M. Li X. Zheng M. Chen L. Li H. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods.Acta Pharm. Sin. B. 2020; 10: 766-788Crossref PubMed Scopus (1505) Google Scholar, 6Gupta A. Zhou H.X. Profiling SARS-CoV-2 main protease (MPRO) binding to repurposed drugs using molecular dynamics simulations in classical and neural network trained force fields.ACS Comb. Sci. 2020; 22: 826-832Crossref PubMed Scopus (25) Google Scholar). However, in vitro studies did not show any inhibitory effect of famotidine on viral proteases (7Loffredo M. Lucero H. Chen D.Y. O’Connell A. Bergqvist S. Munawar A. Bandara A. De Graef S. Weeks S.D. Douam F. Saeed M. Munawar A.H. The in-vitro effect of famotidine on SARS-CoV-2 proteases and virus replication.Sci. Rep. 2021; 11: 5433Crossref PubMed Scopus (18) Google Scholar). The efficacy of famotidine in COVID-19 patients observed in several clinical studies makes it possible that famotidine may affect host pathways in response to viral infection. The histamine H2 receptor targeted by famotidine is not limited to the stomach, but is also found in the brain, the endocrine and exocrine glands, the pulmonary system, and the cardiovascular system. H2 receptors are also present on mast cells (MCs), which are deregulated in viral infections including those caused by coronaviruses (8Kritas S.K. Ronconi G. Caraffa A. Gallenga C.E. Ross R. Conti P. Mast cells contribute to coronavirus-induced inflammation: New anti-inflammatory strategy.J. Biol. Regul. Homeost Agents. 2020; 34: 9-14PubMed Google Scholar, 9Malone R.W. Tisdall P. Fremont-Smith P. Liu Y. Huang X.P. White K.M. L. E. A. E. Wang G. J. Mast and Scholar, T.C. of mast cells with 2021; Full Text Full Text PDF PubMed Scopus Google Scholar). show that famotidine concentrations that are to antagonize H2 receptors on as those on and R.W. Tisdall P. Fremont-Smith P. Liu Y. Huang X.P. White K.M. L. E. A. E. Wang G. J. Mast and Scholar). of to a inflammatory response to a pulmonary cytokine that is in severe COVID-19 infections and may be in mast activation J. 2020; Full Text Full Text PDF PubMed Scopus Google Scholar). release and and in histamine levels in combination with causes in SARS-CoV-2 P. Ronconi G. Caraffa Gallenga C.E. Ross R. S.K. of and and inflammation by or Biol. Regul. Homeost Agents. 2020; 34: Google Scholar, S. Huang S. Wang B. Y. D. A. H. M. K. inflammatory cytokine COVID-19 and 2020; PubMed Scopus Google Scholar, B. M. J. A. F. S. D.Y. M. M. a cytokine response and 2020; Scopus Google Scholar). virus also signaling which causes activation of IRF3 and of and may be in mast activation J. 2020; Full Text Full Text PDF PubMed Scopus Google Scholar). signaling is an antiviral signaling that is in coronavirus infections A. S. A. Toll-like receptor 3 signaling to a response to severe acute respiratory syndrome coronavirus PubMed Scopus Google Scholar). In the which are expressed in cells including cells, and are receptors that several molecular present in and on activation inflammatory and can be on the or in SARS-CoV-2 the the and activates the activation and pathways causes of the and with of and which are for antiviral responses. TLR3-dependent signaling is an response to infections A. Yang Y. The potential of in 2020; PubMed Scopus Google Scholar). is beneficial in the viral may contribute to and cytokine of severe of the disease L. M. G. S.D. C. Toll-like receptors and a with an Sci. 2020; Scopus Google Scholar). In this we the effect of famotidine on viral proteases (SARS-CoV-2 and PLpro) and host cells using computational in vitro and assays and studies show that on famotidine not affect the viral and but host cells by histamine-induced signaling In cells treated with which viral histamine expression to an in the IRF3 and SARS-CoV-2-infected Caco2 cells with famotidine show reduced activation of and levels of the and inflammatory The inhibitory effect of famotidine on signaling can be by cells with the These observations indicate a molecular basis of how of famotidine may in management of histamine-induced inflammation in severe COVID-19 patients. several studies suggested that SARS-CoV-2 may be a of famotidine (5Wu C. Liu Y. Yang Y. Zhang P. Zhong W. Wang Y. Wang Q. Xu Y. Li M. Li X. Zheng M. Chen L. Li H. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods.Acta Pharm. Sin. B. 2020; 10: 766-788Crossref PubMed Scopus (1505) Google Scholar, 6Gupta A. Zhou H.X. Profiling SARS-CoV-2 main protease (MPRO) binding to repurposed drugs using molecular dynamics simulations in classical and neural network trained force fields.ACS Comb. Sci. 2020; 22: 826-832Crossref PubMed Scopus (25) Google we for the of famotidine binding to SARS-CoV-2 by famotidine to the SARS-CoV-2 protein The of binding the of SARS-CoV-2 as (Fig. K. S. J. K. M. S. R. W. A of virus Sci. S. A. PubMed Scopus Google Scholar, D. R. D. D. K. A. L. M. G. A. H. S. protease SARS-CoV-2 viral and 2020; PubMed Scopus Google the is by with and binding also with the of and but with and from the The the of famotidine and the of than the in found potential binding the which with the binding for the of and and (Fig. D. R. D. D. K. A. L. M. G. A. H. S. protease SARS-CoV-2 viral and 2020; PubMed Scopus Google Scholar, M. R. H. Huang of and of the coronavirus Full Text Full Text PDF PubMed Scopus Google Scholar). of famotidine in this may with the binding of However, this binding is the an with and a with The with and to contribute to binding famotidine to the SARS-CoV-2 in we a In this binding is by the in the of the which with the of the protein and the found that the SARS-CoV-2 the of SARS-CoV-2 famotidine no effect on the of the protein (Fig. famotidine did not affect the of SARS-CoV-2 or by the of release from in the of concentrations of the reduced the of SARS-CoV-2 and in the (Fig. famotidine can the binding of to SARS-CoV-2 we the of SARS-CoV-2 with a the of SARS-CoV-2 with no with famotidine (Fig. that famotidine not with or affect in famotidine can affect in cells, we the and the SARS-CoV-2 in cells. with the SARS-CoV-2 in cells. this but famotidine no effect (Fig. studies have shown an inhibitory effect of on the response and on NF-κB signaling D. R. D. D. K. A. L. M. G. A. H. S. protease SARS-CoV-2 viral and 2020; PubMed Scopus Google Scholar, M. R. H. Huang of and of the coronavirus Full Text Full Text PDF PubMed Scopus Google Scholar). SARS-CoV-2 and signaling by expression D. R. D. D. K. A. L. M. G. A. H. S. protease SARS-CoV-2 viral and 2020; PubMed Scopus Google Scholar, B. receptor antagonist famotidine as a therapeutic in 2020; 10: Scopus Google Scholar, X. Yang X. Zheng Y. Yang Y. Y. Chen coronavirus protease inhibits the signaling with the PubMed Scopus Google Scholar). of and IRF3 in SARS-CoV-2 cells treated with causes of this but famotidine has no effect (Fig. and studies, it is that inhibits NF-κB signaling SARS-CoV-2 a inhibitory effect on signaling K. S. J. K. M. S. R. W. A of virus Sci. S. A. PubMed Scopus Google Scholar, D. R. D. D. K. A. L. M. G. A. H. S. protease SARS-CoV-2 viral and 2020; PubMed Scopus Google Scholar). Famotidine treatment no effect on and NF-κB activation in SARS-CoV-2 or cells (Fig. and famotidine did not affect the expression of which are of the or inflammatory signaling in SARS-CoV-2 cells (Fig. these that famotidine not show any effect on the and NF-κB pathways in SARS-CoV-2 cells. Several that the antiviral effect of famotidine on patients is to of the coronavirus main protease K. A. A. M. The coronavirus protease can IRF3 a activation that J. 11: PubMed Scopus Google Scholar). The main protease of SARS-CoV-2 is a protease that to the of It the viral and is for viral has been found to be of the of SARS-CoV-2 of the protease a of in a protease C. B. J.A. Y. T. Zhang X. B. Chen Y. Wang J. and II, SARS-CoV-2 viral replication by the viral main 2020; PubMed Scopus Google Scholar). observed a in treatment with an of the famotidine did not the of (Fig. viral replication in cells treated with famotidine or inhibits the of F. B. K. J. C. L. A. J. G. of in infected with 2020; PubMed Scopus Google Scholar, G. D. C. F. J. L. A. C. P. of SARS-CoV-2 by 2021; PubMed Scopus Google Scholar). no in viral replication or any effect by in cells (Fig. caused a of with (Fig. famotidine is an H2 receptor we that the beneficial of famotidine in patients may be to effect on H2 a effect of famotidine in SARS-CoV-2 infected cells, we the of cells infected with in the of histamine with or famotidine Famotidine treatment to a in several associated with the NF-κB and those associated to signaling (Fig. and network of the using the pathways associated with cytokine viral and signaling to be by famotidine treatment (Fig. a and also in cells, from the these to be to viral (Fig. These suggested that famotidine not affect viral it may affect the antiviral response in infected cells and of of histamine receptors from from cells that expressed histamine and H2 receptors and may be to the effect of histamine and famotidine on H2 receptors (Fig. receptors are an of we to the expression of in SARS-CoV-2-infected cells. Caco2 cells infected with SARS-CoV-2 for an of and (Fig. of with histamine has been to expression of 3 (TLR3) Zhou Zheng Wang of expression and of Toll-like receptor 3 in and cells by PubMed Scopus Google Scholar, G. Wang F. X. Y. Yang H. Li L. of mast receptor 3 expression and release by PubMed Scopus Google Scholar). In cells, treatment with histamine for caused a of and levels (Fig. of these cells with famotidine reduced but did not affect expression (Fig. the effect of viral cells treated with for and expression of by with the expression of including and (Fig. a the virus is present in of we cells with histamine and famotidine and with with histamine to a in which than that caused by effect of histamine and be famotidine present in the (Fig. not affected by treatment or by treatment with 100 histamine or famotidine with an (Fig. The effect of histamine and on expression also with and in for with histamine for to treatment the levels of which by famotidine treatment (Fig. and The effect of histamine on expression is in cells (Fig. These show that and histamine which can be by we the effect of famotidine on with histamine or in combination with famotidine and treated with the to TLR3-dependent signaling (Fig. Histamine not to signaling it can affect treatment signaling of binding kinase and 3 and a in with histamine the activation of the Famotidine counters this effect to a in IRF3 activation and levels (Fig. Histamine and treatment for which be by famotidine (Fig. A effect also on activation after 2 of treatment (Fig. NF-κB activation also in histamine and cells by levels by Histamine and caused an in the of which is reduced on famotidine to expression of and which are of IRF3 and that famotidine reduce levels of these in cells (Fig. these indicate that famotidine may affect and inflammatory which are by viral of we the effect of histamine on expression in cells infected with SARS-CoV-2 infected Caco2 cells of and in cells with (Fig. Famotidine treatment reduced levels but did not affect the expression of the (Fig. In we that viral causes of and NF-κB also that inhibits SARS-CoV-2 and the on IRF3 and signaling in SARS-CoV-2-infected cells D. R. D. D. K. A. L. M. G. A. H. S. protease SARS-CoV-2 viral and 2020; PubMed Scopus Google Scholar). Here we that treatment of and IRF3 in infected cells, famotidine caused a in of IRF3 and NF-κB (Fig. of cells with histamine the of and Famotidine this reducing the of and IRF3 (Fig. cells also an in and which reduced in cells with famotidine (Fig. that the effect of famotidine on the is TLR3-dependent we treated Caco2 cells with the which the of infection. and IRF3 is by histamine and famotidine signaling is by (Fig. and levels are in the of the and is by famotidine treatment (Fig. the molecular famotidine has cellular, not viral targets that the histamine-induced expression of in signaling the IRF3 and NF-κB (Fig. Many drugs are being repurposed to COVID-19 patients and to the of virus Several cohort studies of hospitalized COVID-19 patients a reduced risk for death or intubation with patients (1Freedberg D.E. Conigliaro J. Wang T.C. Tracey K.J. Callahan M.V. Abrams J.A. Famotidine Research GroupFamotidine use is associated with improved clinical outcomes in hospitalized COVID-19 patients: A propensity score matched retrospective cohort study.Gastroenterology. 2020; 159: 1129-1131.e3Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar, T. Gablenz E. Pattinson D. Wang T.C. Conigliaro J. Tracey K. Tuveson D. Famotidine use and quantitative symptom tracking for COVID-19 in non-hospitalised patients: A case series.Gut. 2020; 69: 1592-1597Crossref PubMed Scopus (84) Google Scholar, II, R.B. Hogan III, R.B. Cannon T. Rappai M. Studdard J. Paul D. Dooley T.P. Dual-histamine receptor blockade with cetirizine-famotidine reduces pulmonary symptoms in COVID-19 patients.Pulm. Pharmacol. Ther. 2020; 63: 101942Crossref PubMed Scopus (52) Google Scholar). Famotidine in computational studies it to SARS-CoV-2 (5Wu C. Liu Y. Yang Y. Zhang P. Zhong W. Wang Y. Wang Q. Xu Y. Li M. Li X. Zheng M. Chen L. Li H. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods.Acta Pharm. Sin. B. 2020; 10: 766-788Crossref PubMed Scopus (1505) Google Scholar). However, in vitro assays that famotidine is not an antiviral In cells, famotidine did not viral replication (7Loffredo M. Lucero H. Chen D.Y. O’Connell A. Bergqvist S. Munawar A. Bandara A. De Graef S. Weeks S.D. Douam F. Saeed M. Munawar A.H. The in-vitro effect of famotidine on SARS-CoV-2 proteases and virus replication.Sci. Rep. 2021; 11: 5433Crossref PubMed Scopus (18) Google Scholar). studies also that it not affect SARS-CoV-2 proteases and PLpro) in in vitro as as It also no effect on viral replication in Caco2 cells. A that a combination of famotidine with an receptor antagonist reduces pulmonary symptoms in COVID-19 patients (4Hogan II, R.B. Hogan III, R.B. Cannon T. Rappai M. Studdard J. Paul D. Dooley T.P. Dual-histamine receptor blockade with cetirizine-famotidine reduces pulmonary symptoms in COVID-19 patients.Pulm. Pharmacol. Ther. 2020; 63: 101942Crossref PubMed Scopus (52) Google Scholar). suggested that the beneficial of famotidine may be on cells and signaling controlling host responses. of cells infected with SARS-CoV-2 of to pathways as and cytokine signaling as a of of famotidine treatment and in SARS-CoV-2-infected cells. have been to contribute to inflammatory in acute respiratory distress which is often in severe COVID-19 patients. viral and histamine treatment and The expression of not to in expression with activation of TLR3-dependent pathways and in SARS-CoV-2-infected cells. effect can be by treatment of cells with the effect of famotidine treatment on and protein expression is independent of viral and can be a in cells. However, protein to activation of and of inflammatory and the viral is present to signaling with in cells the effect of histamine on signaling and makes it to famotidine A in IRF3 in infected cells treated with famotidine in the of histamine observed (Fig. Famotidine also levels and can signaling the by of M. C. F. of signaling histamine H2 Pharmacol. PubMed Scopus Google Scholar, T. J. S. H. J. S. Y. M. J. M. T. K. K. and signaling pathways PubMed Scopus (25) Google Scholar). may contribute to of pathways in cells. and studies a effect of histamine treatment on and protein which can be reduced by famotidine A on treated with histamine the be in this of the the of histamine on and G. Wang F. X. Y. Yang H. Li L. of mast receptor 3 expression and release by PubMed Scopus Google Scholar). Famotidine has for histamine H2 receptors and pharmacokinetic show that it can reach concentrations in it can affect neutrophils, and in the which also have H2 to mast activation receptors and may be in mast activation J. 2020; Full Text Full Text PDF PubMed Scopus Google Scholar). inflammatory as and as as mediators as and the of histamine and famotidine in signaling in of expression and pathways in cells infected by These are in how famotidine and may be in reducing in severe COVID-19 patients. SARS-CoV-2 of from SARS-CoV-2 and for expression as D. R. D. D. K. A. L. M. G. A. H. S. protease SARS-CoV-2 viral and 2020; PubMed Scopus Google Scholar). SARS-CoV-2 and from as D. R. D. D. K. A. L. M. G. A. H. S. protease SARS-CoV-2 viral and 2020; PubMed Scopus Google Scholar). E. cells with and in to an of by of with with and with with 2 to 100 2 and for in vitro The expression and of protein and protein protein as M. C. F. of signaling histamine H2 Pharmacol. PubMed Scopus Google Scholar, T. J. S. H. J. S. Y. M. J. M. T. K. K. and signaling pathways PubMed Scopus (25) Google Scholar). The of SARS-CoV-2 from and from A binding protein with The protein the and as Chen C. Profiling of of PubMed Scopus Google Scholar, Chen C. and of for coronavirus J. PubMed Scopus Google Scholar). we the of SARS-CoV-2 with from and by T. The using R. S. B. E. molecular simulations from to Scopus Google Scholar). The famotidine, from T. discovery for PubMed Scopus Google and using the The to the using the with the of the A. a based on PubMed Scopus Google Scholar). The of the resulting in These binding using the with a of 3 as in the of R. S. B. 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S. protease SARS-CoV-2 viral and 2020; PubMed Scopus Google Scholar). SARS-CoV-2 from from to using cells. as in cells in Caco2 cells with 100 histamine and famotidine for by with SARS-CoV-2 for cells in protease to for with and in with the of and the of and after to a of M. using acid using and of in to with The by of to a of and for an in and to the in and in for in on an to an with a on an and a which been in with and using an by a from to by an to in which for a resolution of a of 100 and an of to with in 2 and using a with a of of and using with a of on the an of and 2 using of and in the with the resolution of and a of with using as a and of by the of of is and of is the and protein SARS-CoV-2 February from in as as as in with the the and as as as of and the protein with a discovery of on and protein to the protein in and by using the in for and as for present in from of using using with and of protein a protein for and with using the Y. Zhou B. L. M. A.H. C. S.K. a for the of 10: PubMed Scopus Google Scholar). of cells in infected with SARS-CoV-2 a of with famotidine and in with with drug after infection. and with an the protein of by with a and the of for for using for and cells in protease In protein in which for by to membrane for 2 and with the and for this IRF3 NF-κB the of and NF-κB a in cells. In an expression the and the or NF-κB In 100 of a in and the of is shown in after cells treated with histamine and famotidine for this using for and for NF-κB expression using the by taking cells as cells treated with 100 histamine and Famotidine for by treatment with for with in and with using the system. of a of with a in to and are of cells from independent indicate SARS-CoV-2 from using to the In to using using using and the for and are as of these the to in based on the of cells treated with or of in a in indicate by in from the of the of and that of from the of and treated in expression by of in indicate by in The in has been to the the with the the in the are from the The that have no of with the of this to for with the for and D. and A. for R. M. and D. A. D. A. R. D. and D. D. R. A. R. D. K. S. H. W. L. J. and D. R. A. A. R. and P. P. G. D. P. P. G. J. H. K. S. and D. G. H. W. L. K. S. G. and D. R. M. and D. R. M. R. M. R. A. D. A. R. D. K. S. W. L. K. S. 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