Efficacy and safety of dolutegravir/lamivudine in virologically suppressed female participants: week 48 data from the pooled TANGO and SALSA studies.

OBJECTIVES: Women represent >50% of people with HIV globally but have historically been underrepresented in clinical trials. We evaluated the efficacy and safety of switching to dolutegravir/lamivudine (DTG/3TC) vs continuing their current antiretroviral regimen (CAR) by sex assigned at birth (female and male) in virologically suppressed adults with HIV-1 without prior virological failure in a pooled analysis of two randomized controlled trials. METHODS: This analysis included 48-week data from the phase 3 TANGO and SALSA studies. Primary and key secondary endpoints included proportions of participants with HIV-1 RNA ≥50 and <50 copies/mL at week 48, respectively. Safety was also assessed. RESULTS: Of 1234 participants, 250 (DTG/3TC, n = 133; CAR, n = 117) were female at birth. Week 48 proportions of participants with Snapshot HIV-1 RNA ≥50 copies/mL were similar regardless of sex at birth (DTG/3TC vs CAR: female, <1% [1/133] vs 2% [2/117]; male, <1% [1/482] vs <1% [3/502]). Proportions with HIV-1 RNA <50 copies/mL were high across sexes and treatment groups (DTG/3TC vs CAR: female, 91% [121/133] vs 89% [104/117]; male, 94% [455/482] vs 94% [471/502]). Immunological response with DTG/3TC was slightly higher in female participants. Incidences of adverse events leading to withdrawal and serious adverse events were low and comparable between treatment groups and across sexes. Weight gain was higher with DTG/3TC than with CAR among female participants aged ≥50 years (treatment difference 2.08 kg [95% confidence interval 0.40-3.75]). CONCLUSIONS: Results confirm the robustness of DTG/3TC as a switch option in virologically suppressed females with HIV-1, with outcomes similar to those in males.

Dolutegravir: clinical and laboratory safety in integrase inhibitor-naive patients.

BACKGROUND: The efficacy of dolutegravir (DTG) has been demonstrated in 5 randomized studies in integrase inhibitor (INI)-naive adult populations. To date, a detailed safety review of DTG has not been provided in the literature. OBJECTIVE: To describe the safety and tolerability profile of DTG in adults based on 5 randomized, controlled trials and comparison with drugs in 3 major antiretroviral (ARV) classes. METHODS: Safety data from phase IIb/III/IIIb trials in ART-naive and ART-experienced, INI-naive adults were integrated. RESULTS: In 4 ART-naive (SPRING-1, SPRING-2, SINGLE, FLAMINGO) and 1 ART-experienced, INI-naive study (SAILING), 1,579 individuals received a DTG-containing regimen. The proportion of individuals from DTG treatment arms who withdrew due to adverse events (AEs) was low (≤2%) compared to raltegravir (RAL; 2% SPRING-2, 4% SAILING), efavirenz (EFV)-containing comparator arm (10% SINGLE), and darunavir + ritonavir (DRV/r; 4% FLAMINGO). The most frequently observed AEs (diarrhea, nausea, headache), typically grade 1 or 2 in severity, did not lead to study discontinuation. Psychiatric and nervous system disorders with DTG were comparable to RAL- and DRV/r-containing regimens and favorable to EFV-containing regimens. In hepatitis B and/or C coinfected ART-naive individuals, the incidence of transaminase elevations was lower with DTG versus RAL and EFV comparators, but was similar to DRV/r. In SAILING, transaminase elevations were more commonly observed with DTG, particularly in the setting of inadequate hepatitis B therapy or immune reconstitution. On DTG treatment, mild creatinine elevations occurred and stabilized early. Few cases of hypersensitivity reaction and/or severe rash were seen. Rates of these events were comparable to or lower than with RAL-, EFV-, and DRV/r-containing regimens. CONCLUSIONS: The safety profile for DTG 50 mg once daily in INI-naive individuals was comparable to RAL- and DRV/r-containing regimens and generally favorable compared with EFV-containing regimens.

Tool for automatic macrozone characterization from EBSD data sets of titanium alloys.

Microtexture heterogeneities are commonly found in titanium forgings because of the thermomechanical processing. Also known as macrozones, these regions can reach millimetres in length, with grains sharing a similar crystallographic orientation leading to less resistance to crack propagation. Since the link between macrozones and the reduction of cold-dwell-fatigue performance on rotative components in gas turbine engines was established, efforts have been put into macrozone definition and characterization. The electron backscatter diffraction (EBSD) technique, widely used for texture analysis, allows for a qualitative macrozone characterization; however, further processing is required to define the boundaries and disorientation spread of each macrozone. Current approaches often use c-axis misorientation criteria, but this can sometimes lead to a large disorientation spread within a macrozone. This article describes the development and application of a computational tool implemented in MATLAB for automatic macrozone identification from EBSD data sets on the basis of a more conservative approach where both the c-axis tilting and rotation are considered. The tool allows for detection of macrozones according to the disorientation angle and density-fraction criteria. The clustering efficiency is validated by pole-figure plots, and the effects of the key parameters defining the macrozone clustering (disorientation and fraction) are discussed. In addition, this tool was successfully applied to both fully equiaxed and bimodal microstructures of titanium forgings.

Oral manifestations of lupus.

INTRODUCTION: Mucosal involvement is commonly seen in patients with lupus; however, oral examination is often forgotten. Squamous cell carcinoma arising within oral lupoid plaques has been described, emphasizing the importance of identifying and treating oral lupus. METHODS: We undertook a retrospective single-centre study looking at oral findings in patients attending our multidisciplinary lupus clinic between January 2015 and April 2016. RESULTS: A total of 42 patients were included. The majority of patients were female (88%) and had a diagnosis of discoid lupus erythematosus (62%). Half of the patients had positive oral findings, 26% had no oral examination documented, and 24% had documented normal oral examinations. CONCLUSION: Our findings suggest that oral pathology is common in this cohort of patients. Regular oral examination is warranted to identify oral lupus and provide treatment. Associated diseases such as Sjogren's syndrome may also be identified. Patients should be encouraged to see their general dental practitioners on a regular basis for mucosal review. Any persistent ulcer that fails to respond to treatment or hard lump needs urgent histopathological evaluation to exclude malignant transformation to squamous cell carcinoma.

Recurrence of Kawasaki disease in an adult patient with cholecystitis.

We report recurrence of Kawasaki disease in a 20-year-old man eighteen years after the primary episode. Athough sixty-nine cases have been reported among adults in the literature, this represents only the second case of Kawasaki disease recurring in an adult patient after childhood presentation. Our patient presented with the characteristic mucocutaneous features, fever, arthralgia, epigastric pain and cholecystitis. His presentation was complicated by arthralgias and abnormal liver function tests, which are more common in the adult patient. The diagnosis was made based on clinical findings after the exclusion of other causes of persistent febrile illness. He was successfully treated with high dose aspirin and intravenous immunoglobulin therapy. Despite a second presentation of Kawasaki disease our patient did not have any demonstrable coronary arterial involvement. Although typically a self-limiting disease, cardiac complications can cause significant morbidity and mortality in those not treated with aspirin and IVIG. This report serves to highlight that late recurrence of Kawasaki disease may develop in adults many decades after the initial presentation. A twenty-year-old male, presented to the Emergency department with a one-week history of general malaise. He complained of sore throat, 5-day history of fever (39 degree celsius), epigastric discomfort, rash, nausea, vomiting, generalised arthralgia and myalgia. He was jaundiced with dark urine and pale stools. He had been commenced on oral penicillin three times a day for possible streptococcal infection after the rash had occurred. Past medical history was notable for a previous episode of Kawasaki disease (KD) at 2 years of age, after which there were no adverse sequelae, a history of asthma and non-alcoholic fatty liver disease.

Bacteriologic findings associated with chronic bacterial maxillary sinusitis in adults.

An open-label, multicenter study was performed to assess bacteriologic findings associated with chronic bacterial maxillary sinusitis in adults. Seventy aerobic (52.2%) and 64 anaerobic (47.8%) pathogens were recovered from clinically evaluable patients at baseline (before therapy). The most commonly isolated anaerobes were Prevotella species (31.1%), anaerobic streptococci (21.9%), and Fusobacterium species (15.6%). The aerobes most frequently recovered included Streptococcus species (21.4%), Haemophilus influenzae (15.7%), Pseudomonas aeruginosa (15.7%), and Staphylococcus aureus and Moraxella catarrhalis (10.0% each). Recurrences of signs or symptoms of bacterial maxillary sinusitis associated with anaerobes were twice as frequent as were those associated with aerobes when counts of anaerobes were > or =10(3) cfu/mL. A pathogenic role for Granulicatella species in cases of chronic sinusitis was documented for the first time.

Cefsulodin kinetics in healthy subjects after intramuscular and intravenous injection.

We evaluated cefsulodin kinetics in normal subjects after 250-, 500-, and 1,000-mg, intramuscular injections and 500-, 1,000-, and 2,000-mg 30-min intravenous infusions. Twelve plasma and four urine samples were collected in the first 12 and 24 hr. Plasma samples were analyzed by a new, highly precise high-performance liquid chromatographic procedure developed in our laboratory and urine samples were analyzed microbiologically, using Pseudomonas aeruginosa as the test organism. Mean calculated peak plasma levels from the 250-, 500-, and 1,000-mg intramuscular doses were 5.46, 11.81, and 19.40 microgram/ml. After 500-, 1,000-, and 2,000-mg intravenous infusions peak levels were 32.7, 65.7, and 190.1 microgram/ml. Data from the intramuscular doses were fitted to a one-compartment open kinetic model, yielding a mean elimination half-life (t1/2) of 1.9 hr. Data from the intravenous infusions were fitted to a two-compartment open model, with a mean beta-phase t1/2 of 1.6 hr. Mean 0- to 24-hr urinary recoveries after the three intramuscular doses were 50.0%, 54.5%, and 51.2% of total dose; after the three intravenous doses they were 60.4%, 52.4%, and 54.0%. Cefsulodin kinetics were shown to be consistent and orderly.

Dopaminergic innervation of the telencephalon of the pigeon (Columba livia): a study with antibodies against tyrosine hydroxylase and dopamine.

The dopaminergic structures in the telencephalon of the pigeon were investigated with antisera against glutaraldehyde-conjugated dopamine (DA) and tyrosine hydroxylase (TH). Our goal was to describe the morphological patterns of the labelled axons and to provide a detailed map of the density and regional distribution of the dopaminergic innervation in relation to cytoarchitectonic areas. DA- and TH-like fibers reached their highest density in the paleostriatum augmentatum and the lobus parolfactorius of the basal ganglia. The paleostriatum primitivum was characterized by a dichotomous DA-positive innervation with a diffuse fiber network contacting enpassant granular cells and a more specific input that completely wrapped up large cells, which probably represent relay neurons. Two distinct DA-positive pathways could be followed back from the forebrain leading to the dopaminergic cell groups of the nucleus tegmenti pedunuculopontinus pars lateralis and the area ventralis tegmentalis. The primary sensory areas of the visual, auditory, somatosensory, and trigeminal systems within the forebrain of the pigeon were virtually devoid of DA-like fibers and demonstrated only TH-positive axons, probably of a noradrenergic nature. Among the limbic structures, the neostriatum caudolaterale (a possible equivalent of the mammalian prefrontal cortex), the septum, the nucleus accumbens, and parts of the archistriatum were heavily labelled by DA-like axons. A highly characteristic morphological feature of the catecholaminergic innervation was the presence of "baskets," which are constituted by TH- and DA-positive fibers coiled up around large perikarya, so that the surrounded somata were virtually visible by the presence of labelled axons. The density of basket and nonbasket type innervations seemed to be independently regulated, so that each forebrain structure could be characterized by a mixture consisting of the individual degrees of these two features. Our results demonstrate that the dopaminergic innervation of the forebrain of the pigeon is widespread but shows important regional variations. Similar to mammals, associative and motor structures are heavily innervated by dopaminergic fibers, whereas sensory areas are dominated by their noradrenergic input. The basket and nonbasket type innervations observed in virtually all of these subdivisions of the telencephalon may indicate the presence of two main classes of catecholaminergic afferents with different mechanisms of modulation of forebrain activity patterns.

Bacteriologic and clinical efficacy of high dose amoxicillin/clavulanate in children with acute otitis media.

OBJECTIVES: To determine the bacteriologic and clinical efficacy of high dose amoxicillin/clavulanate (90/6.4 mg/kg/day) against common bacterial pathogens causing acute otitis media (AOM), including penicillin-resistant Streptococcus pneumoniae (PRSP). METHODS: In this open label multicenter study, 521 infants and children with AOM [mean age, 18.6 months; age < 24 months, n = 375 (72%)] were treated with amoxicillin/clavulanate 90/6.4 mg/kg/day in two divided doses for 10 days. Bilateral otitis media, previous episodes of AOM, antibiotic treatment within 3 months and day-care attendance were recorded in 60.1, 35.7, 50.2 and 38.2% of the children, respectively. Tympanocentesis was performed before the first dose and repeated on Days 4 to 6 for all children with S. pneumoniae at 22 centers and for all children with any pathogen at 3 centers. Clinical response was assessed at end of therapy. RESULTS: Pathogens were isolated from 355 (68%) of 521 enrolled children; 180 children underwent repeat tympanocentesis and were bacteriologically evaluable. Baseline pathogens were S. pneumoniae (n = 122 enrolled/93 bacteriologically evaluable), Haemophilus influenzae (n = 160/51), both (n = 37/32) and others (n = 36/4). Pathogens were eradicated from 172 (96%) of 180 bacteriologically evaluable children. Overall 122 (98%) of 125 isolates of S. pneumoniae were eradicated, including 31 (91%) of 34 PRSP isolates (penicillin MICs 2 to 4 micrograms/ml). Seventy-eight (94%) of 83 isolates of H. influenzae were eradicated. Symptoms and otoscopic signs of acute inflammation were completely resolved or improved on Days 12 to 15 in 263 (89%) of 295 clinically evaluable children with bacteriologically documented AOM. CONCLUSIONS: On the basis of bacteriologic outcome on Days 4 to 6 and clinical outcome on Days 12 to 15, we found that high dose amoxicillin/clavulanate (90/6.4 mg/kg/day) was highly efficacious in children with AOM, including those most likely to fail treatment, namely children < 24 months of age and those with infectious caused by PRSP.

Somatostatin and substance P-like immunoreactivity in the auditory brainstem of the adult rat.

The superior olivary complex (SOC) of the adult rat brainstem was studied in detail with regard to its innervation by neural elements showing immunoreactivity for two neuroactive peptides, somatostatin and substance P. Nerve fibres and varicosities showing positive immuno-reactivity for both peptides were particularly dense immediately dorsal and lateral to the lateral superior olivary nucleus (LSO) and dorsal to the superior paraolivary nucleus (SPN). Penetration of this curtain-like innervation into the SPN was limited, and the LSO showed only a very minor innervation by somatostatin-positive structures in its most medial (high frequency) lobe. Dense fibre labelling and varicosities were also apparent for both peptides immediately medial to the ventral and dorsal nuclei of the lateral lemniscus, and in the external cortex and dorsomedial zones of the inferior colliculus (IC). Labelled fibres and endings were also seen in the granule cell regions of anteroventral cochlear nucleus (AVCN) and the most dorsomedial parts of the dorsal cochlear nucleus (DCN). The majority of cells in the medial nucleus of the trapezoid body (MNTB) showed a prominent innervation by nerve terminals that stained positive for somatostatin only whereas the medial superior olivary nucleus (MSO) was devoid of label for both peptides. The ventral nucleus of the trapezoid body (VNTB) showed sparse but significant innervation by both somatostatin and substance P-positive structures. Hence the VNTB was the only defined nucleus of the SOC to show a significant substance P-positive innervation. Neuronal somata immuno-reactive for somatostatin were found in anteroventral and posteroventral cochlear nuclei (AVCN and PVCN) and the A5 and A7 cell groups adjacent to the LSO and the VNLL and DNLL and in all subdivisions of the inferior colliculus (IC). Somata showing only faint immunoreactivity for substance P were found in the VNLL, AVCN and PVCN. These results suggest a potential role for both peptides in auditory signal processing in the adult rat brain.

Neurotransmitter and neuromodulator systems of the rat inferior colliculus and auditory brainstem studied by in situ hybridization.

This study was concerned with the distribution of a variety of putative neuromodulator and neurotransmitter systems in auditory regions of the rat brainstem using in situ hybridization histochemistry. Serial brain sections were screened for the presence of mRNAs for (i) precursors of the neuroactive substances cholecystokinin, somatostatin, proenkephalin and substance P (preprotachykinin), (ii) glutamic acid decarboxylase, the key synthesizing enzyme for GABA, or (iii) subunits alpha 1, alpha 2 and alpha 3 of the GABAA receptor. Detectable message for all of these probes was found in at least one auditory brainstem area. There were clear differences in the distribution of the various mRNAs in subregions of the inferior colliculus, superior olivary complex, lateral lemniscus and cochlear nucleus. Cells expressing mRNA for glutamic acid decarboxylase were most prominent in the inferior colliculus, but were also present in all lower auditory brainstem nuclei, except the medial superior olivary nucleus and medial nucleus of trapezoid body. The mRNA for GABAA alpha 1 receptor subunits was detectable in all auditory regions investigated, although at different levels of expression. GABAA alpha 2 and alpha 3 mRNA signals were seen in inferior colliculus, lateral lemniscus and in almost all superior olivary complex regions, but in fewer cells and at lower levels than the GABAA alpha 1 subtype. Moderate to high levels of preprocholecystokinin mRNA expression were seen in all subregions of the inferior colliculus. In other auditory brainstem areas, preprocholecystokinin mRNA levels were either low or absent. With regard to mRNAs for the neuroactive peptides somatostatin, preprotachykinin and preproenkephalin, all were expressed in the inferior colliculus but there were differences in their cellular distribution. For example, there were almost no preprotachykinin mRNA expressing cells in the central nucleus of inferior colliculus and levels of somatostatin mRNA were especially high in the dorsal cortex and in layer 3 of the external cortex of inferior colliculus. There were also differences in the pattern of expression of these mRNAs in the various brainstem auditory nuclei; there was no preprotachykinin mRNA in any part of the superior olivary complex, only somatostatin mRNA was found in the ventral cochlear nucleus, and expression of preproenkephalin mRNA was pronounced in the ventral nucleus of the trapezoid body and the rostral periolivary zone. The data are considered in light of the connectivity and functional organization of the auditory brainstem.

Sensitization to apomorphine in pigeons: unaffected by latent inhibition but still due to classical conditioning.

When administered apomorphine, pigeons exhibit protracted bouts of pecking behavior. This response is subject to sensitization, as it initially increases with repeated drug injections. The hypothesis is examined that the sensitization is due to a Pavlovian conditioning of the drug-induced pecking to the environment in which it first takes effect. In a first experiment, we attempted to suppress this conditioning by extensively pre-exposing the birds to the test environment and saline injections (latent inhibition procedure). As the experiment yielded undiminished sensitization, it cast doubt on the conditioning hypothesis. However, while inhibitory pretraining also proved ineffective in a second experiment, a shortening of response latencies specific to the environment in which the animals had first experienced the apomorphine effect supported the conditioning hypothesis. It is suggested that the absence of latent inhibition may be due to the interference of a context-dependent conditioning effect. A third experiment that examined the hypothesis that the reinforcing properties of apomorphine might be attributable to its well known anorectic properties. The results provided some support for this notion. At the same time, they also confirmed that apomorphine-induced pecking conditions reliably to environmental cues. These cues are then by themselves capable of provoking conditioned pecking.

Caffeine citrate for the treatment of apnea of prematurity: a double-blind, placebo-controlled study.

STUDY OBJECTIVE: To evaluate the efficacy and safety of caffeine citrate for treatment of apnea of prematurity. DESIGN: Multicenter, parallel, randomized, double-blind, placebo-controlled trial with open-label rescue. SETTING: Nine neonatal intensive care units. PATIENTS: Eighty-five infants, 28-32 weeks postconception and 24 hours or more after birth who had six or more apnea episodes within 24 hours. INTERVENTION: Caffeine citrate 10 mg/kg (as caffeine base) administered intravenously, followed by 2.5 mg/kg/day orally or intravenously, or placebo, for up to 10 days. Infants failing double-blind therapy could receive open-label rescue. MEASUREMENTS AND MAIN RESULTS: Success was defined as 50% or greater reduction in apnea episodes and elimination of apnea. Caffeine citrate was significantly more effective than placebo in reducing apnea episodes by at least 50% in 6 days (p<0.05), and approached statistical significance (p<0.10) in 3 days. It was significantly better than placebo in eliminating apnea in 5 days (p<0.05), and approached significance (p<0.10) in 2 days. The number of infants with an aggregate of 7-10 days of at least a 50% reduction in apnea events or elimination of apnea was significantly higher in the caffeine citrate than in the placebo group. Adverse events did not differ significantly between groups. No correlations were found between success and mean daily plasma concentrations or baseline characteristics. Volume of distribution and clearance increased with weight, supporting weight-adjusted dosing of caffeine citrate. CONCLUSION: Caffeine citrate 10 mg/kg caffeine base (equivalent to 20 mg/kg caffeine citrate) intravenously followed by 2.5 mg/kg/day caffeine base (equivalent to 5 mg/kg/day caffeine citrate) either intravenously or orally for 10 days is safe and effective for treating apnea of prematurity in infants 28-32 weeks postconception.

Frontal forebrain lesions: effects on the foraging and apomorphine pecking of pigeons.

The role of the nucleus basalis prosencephali (Bas), a frontal forebrain structure peculiar to birds, in the control of forage pecking and apomorphine-induced pecking was investigated. In a quasi-natural grit-grain selection task bilateral coagulations of the Bas and the associated neostratum frontolaterale (Nfl) caused a marked fall in grain per peck uptake and a simultaneous increase in grit per peck uptake. Bas lesions also had a reducing effect on the compulsive pecking elicited by systemic injections of apomorphine. This confirms that the Bas is involved in the control of forage pecking and dopaminergic pecking of birds.

Geographic and seasonal variation in Mycobacterium avium bacteremia among North American patients with AIDS.

Analysis of geographic risk was performed for Mycobacterium avium complex (MAC) bacteremia among North American patients with AIDS. Monthly mycobacterial blood cultures were taken from patients who were placebo recipients in a prospective evaluation of MAC prophylaxis. Of 571 patients, 102 (17.9%) acquired MAC bacteremia during an average follow-up of 256 days. The area with the highest risk for MAC was the South Central region (27.9%; P < 0.02), whereas the area with the lowest risk was Canada (11.3%; P = 0.12). When the southern states were combined and compared with the northern states and Canada, the incidence of MAC bacteremia was higher in the southern states (21.6% versus 14.0%, P < 0.03). Proportional hazards analysis was performed for the difference between the North and South and controlled for baseline CD4 cell count. In this analysis, time to MAC was significantly longer in the North (hazard ratio = 0.587, 95% confidence interval 0.390 to 0.883, P = 0.01). Although overall variation in seasonality was not marked, there was a significant decrease in cases in the North during the summer months (P < 0.01). We conclude that geographic location is a risk factor for MAC bacteremia in patients with advanced AIDS, with decreased risk in northern North America.

Increased cavernosal relaxation by Phoneutria nigriventer toxin, PnTx2-6, via activation at NO/cGMP signaling.

Erectile dysfunction (ED) mechanisms in diabetic patients are multifactorial and often lead to resistance to current therapy. Animal toxins have been used as pharmacological tools to study penile erection. Human accidents involving the venom of Phoneutria nigriventer spider are characterized by priapism. We hypothesize that PnTx2-6 potentiates cavernosal relaxation in diabetic mice by increasing cyclic guanosine monophosphate (cGMP). This effect is neuronal nitric oxide synthase (nNOS) dependent. Cavernosal strips were contracted with phenylephrine (10(-5) M) and relaxed by electrical field stimulation (20 V, 1-32 Hz) in the presence or absence of PnTx2-6 (10(-8) M). Cavernosal strips from nNOS- and endothelial nitric oxide synthase (eNOS)-knockout (KO) mice, besides nNOS inhibitor (10(-5) M), were used to evaluate the role of this enzyme in the potentiation effect evoked by PnTx2-6. Tissue cGMP levels were determined after stimulation with PnTx2-6 in presence or absence of N-nitro-L-arginine methyl ester (L-NAME) (10(-4) M) and ω-conotoxin GVIA (10(-6) M), an N-type calcium channel inhibitor. Results showed that PnTx2-6 enhanced cavernosal relaxation in diabetic mice (65%) and eNOS KO mice, but not in nNOS KO mice. The toxin effect in the cavernosal relaxation was abolished by nNOS inhibitor. cGMP levels are increased by PnTx2-6, however, L-NAME abolished this enhancement as well as ω-conotoxin GVIA. We conclude that PnTx2-6 facilitates penile relaxation in diabetic mice through a mechanism dependent on nNOS, probably via increasing nitric oxide/cGMP production.