The presentation is antepartum haemorrhage. Ultrasound should be performed to find the reason for bleeding and assess the fetal well being.

There is evidence that folic acid, iodine and vitamin D are important for reproductive outcomes. Folic acid and iodine supplementation is recommended for women planning to conceive and in pregnancy.

The recommended dose of folic acid for women without special considerations planning to conceive is 400-500 mcg. The recommended dose of folic acid for women with special considerations is 2-5 mg per day.

Women planning a pregnancy, including those with thyroid disease, should take iodine supplements in the dose of 150 mcg per day prior to and during pregnancy.

This patient is towards the end of the first stage of labour and is having complications. Labour is divided into 3 stages. The first stage begins at regular uterine contractions and ends with complete cervical dilatation at 10 cm. It has a latent phase and an active phase- The active phase is usually considered to have begun when cervical dilatation reaches 4 cm. So this patient is in the active phase of the first stag- The second stage begins with complete cervical dilatation and ends with the delivery of the foetus. The third stage of labour is the period between the delivery of the foetus and the delivery of the placenta and fetal membranes.

This patient’s contractions seem adequate and yet the fetal heart tone with baseline 80/min and absent variability suggests fetal distress. This is category III of the fetal heart rate pattern because the baseline rate is < 110/min with absent variability. It is usually predictive of abnormal acid-base status. The recommended actions are maternal position change and oxygen administration, discontinuation of labour stimulus such as oxytocin, treatment of possible underlying conditions, and expedited delivery.
→ Magnesium sulphate infusion is mainly used to prevent eclamptic seizures and despite no evidence of its effectiveness as a tocolytic agent, it is used sometimes to reduce risks of preterm birth.
→ Fetal scalp pH monitoring would help determine if there is indeed an acidosis and should be done before deciding whether a Caesarean section is necessary, but maternal position change and oxygen administration should be done first.
→ Ultrasonography may be used for preinduction cervical length measurement or if the active stage has already started- It is considered more accurate than digital pelvic exam in the assessment of fetal descent; however, at this point maternal position change and oxygen administration should be done first.
→ Immediate Caesarean section would be done if fetal scalp pH monitoring revealed a pH < 7.20. At this point, the best next step is maternal position change and oxygen administration.

Trauma is a major contributor for maternal mortality and is one of the leading causes of pregnancy-associated maternal deaths.

As a result of maternal hypotension or hypoxemia, placental abruption, uterine rupture or fetal trauma a maternal trauma can compromise the fetus also.
Patient’s bruises on the abdomen which are seatbelt marks, are indications that this woman has positioned the seat belt incorrectly over the uterus. So there is a good chance that the uterus and its contents, including the fetus, has been affected by the impact. In a pregnant woman, the correct position of seat belt is when the lap belt is placed on the hip below uterus and the sash is placed between breasts and above the uterus.

A minimum of 24-hour period monitoring is recommended for all pregnant women, apart from the routine trauma workup indicated in non-pregnant women, in case they have sustained trauma in the presence of any of the following:
– Regular uterine contractions
– Vaginal bleeding
– A non-reassuring fetal heart rate tracing
– Abdominal/uterine pain
– Significant trauma to the abdomen

Considering the bruises over her abdomen this patient should be considered as having significant abdominal trauma and must be kept under observation for a minimum of 24 hours. Such patients should not be discharged unless the clinician makes sure they do not have any complications like abruption or preterm labor.

Dizygotic twin pregnancies are known to increase with age of the mother. Naturally conceived twins are thought to occur in a 0.3% rate in women under 25 years, 1.4% between 25 and 34, 3% between 34 and 39, and 4.1% in women in their 40s or over. We also know that at least 50% of all twin pregnancies are conceived through ART and that this proportion is probably higher for women in their 40s.

Threatened miscarriage is a term used to describe any abnormal vaginal bleeding that occurs in first trimester, sometime associated with abdominal cramps. The cervix remains closed and the pregnancy may continue as normal.

Patient mentioned in the given case has developed clinical features of cervical insufficiency and the possible treatment options include:
1- Cerclage, which is the technique used for the reinforcement of cervical ring with nonabsorbable suture material and is indicated based on ultrasonographic findings. It is the treatment of choice when cervical shortening is detected by ultrasonography before 22 to 24 weeks of gestation.

2- Vaginal progesterone is used to reduce the risk of preterm delivery in women who have a prior history of idiopathic preterm delivery or cervical shortening, which is confirmed in the current pregnancy also by ultrasonography.This method is applicable only to those women who do not meet the criteria for Cerclage.

All the other options of management are incorrect in the given case.

Chickenpox or varicella is a contagious disease caused by the varicella-zoster virus (VZV). The virus is responsible for chickenpox (usually primary infection in non-immune hosts) and herpes zoster or shingles (following reactivation of latent infection). Chickenpox results in a skin rash that forms small, itchy blisters, which scabs over. It typically starts on the chest, back, and face then spreads. It is accompanied by fever, fatigue, pharyngitis, and headaches which usually last five to seven days. Complications include pneumonia, brain inflammation, and bacterial skin infections. The disease is more severe in adults than in children.

Primary varicella infection during pregnancy can also affect the foetus, who may present later with chickenpox. In pregnant women, antibodies produced as a result of immunization or previous infection are transferred via the placenta to the foetus. Varicella infection in pregnant women could spread via the placenta and infect the foetus. If infection occurs during the first 28 weeks of pregnancy, congenital varicella syndrome may develop. Effects on the foetus can include underdeveloped toes and fingers, structural eye damage, neurological disorder, and anal and bladder malformation.

Prenatal diagnosis of fetal varicella can be performed using ultrasound, though a delay of 5 weeks following primary maternal infection is advised.

Antivirals are typically indicated in adults, including pregnant women because this group is more prone to complications.

Organisms frequently associated with obstetric sepsis include: beta haemolytic streptococci, Gram-negative rods such as Escherichia coli, Streptococcus pneumoniae and influenza A and B.

E. coli is the most common sepsis pathogen in pregnancy.

Heparin is a large-sized molecule and does not cross the placenta; it can provide anticoagulation in the mother, however, has no effect on the baby. Heparin is the preferred anticoagulant therapy during pregnancy.
Moreover, the anticoagulant effect of heparin can be rapidly reversed by protamine sulphate.
Warfarin, a coumarin derivative, takes much longer to be reversed compared to heparin. This can be given to the mother between 13 and 36 weeks of pregnancy, however, should be avoided in the first trimester due to its teratogenic effects.
The anticoagulant effect of coumarin derivatives on the baby also takes longer to be reversed.

The most suitable step would be to wait for spontaneous onset of labour. This woman would be able to deliver vaginally in 3 situations. The first would be if the foetus is estimated to weigh less than 3800g (first child weight 3800g). Another would be if the foetus is in a frank or complete breech presentation and lastly if the rate of labour progress is satisfactory and breech extraction is unnecessary. RCOG (Royal College of Obstetricians & Gynaecologists) guidelines recommends that women should be informed that elective Caesarean section for the delivery of a breech baby would have a lower risk of perinatal mortality than a planned vaginal delivery. This is because with an elective Caesarean section, we would be able to avoid stillbirth following 39 weeks of gestation as well as intrapartum and vaginal breech delivery risks. The ideal mode of delivery of a breech foetus when labour starts or at least close to term is a Caesarean section as the risks towards the foetus would be significantly increased in a vaginal delivery. The obstetrician is responsible to ensure that there are no other abnormalities that could complicate this even further such as footling presentation, low estimated birth weight (less than 10th centile), hyperextended neck on ultrasound, evidence of fetal distress and high estimated birth weight (>3.8kg). Provided that there is a normal progression of events, fetal risks during both labour and delivery should be low if such factors are absent. Hence, it is right to await the onset of labour to occur spontaneously in this case. In order to exclude a knee presentation with fetal head extension or a footling breech, ultrasound examination has to be done. These are linked to a high fetal risk if the mother attempts vaginal delivery. X-ray pelvimetry is advisable but is not essential in fetal size assessment since its accuracy is roughly 20%. In this case, it is not indicated since there is evidence that her pelvis is of adequate size as she had already delivered a 3.9kg baby prior. It is best to avoid induction of labour in breech cases for numerous reasons (need for augmentation, cord prolapse).

Levonorgestrel, also known as the morning-after pill, is a first-line oral emergency contraceptive pill with approval from the World Health Organization to prevent pregnancy. It is FDA-approved to be used within 72 hours of unprotected sexual intercourse or when a presumed contraceptive failure has occurred.

A prescription is not needed, and it is available over the counter at local pharmacies. The FDA has also approved levonorgestrel availability for all age groups due to its lack of life-threatening contraindications and side-effect profile.

There are several contraindications for the emergency contraceptive form, including allergy, hypersensitivity, severe liver disease, pregnancy, and drug-drug interactions with liver enzyme-inducing drugs. The medication is not for use in women confirmed to be pregnant; however, there is no proof nor reports of adverse effects on the mother or foetus following inadvertent exposure during pregnancy.

Extreme headache, vision defects, such as blurring of the eyes, rib pain, sudden swelling of the face, hands or feet are all consistent with pre-eclampsia. Women with the mentioned symptoms should have their blood pressure checked immediately. They should also be checked for proteinuria. Diarrhoea is not related to pre-eclampsia. Pruritus would be more related to pregnancy cholestasis. Meanwhile, bruising and abnormal LFTs are common in complicated pre-eclampsia but not in an uncomplicated one.

Patient mentioned above is a known case of type 2 diabetes which makes her at high risk of having neural tube defects. She should be advised to start taking a high dose of (5mg) folic acid supplement daily for at least 1-month prior to conception and it should be continued upto 12 weeks of her pregnancy.

Folate, which is a water-soluble B vitamin, is usually obtained from diet or through supplementation. For those patients with a history of type 2 diabetes mellitus, who are planning for pregnancy, high doses are recommended to prevent any possible neural tube defects.

Vitamin A is not safe and should be avoided in pregnancy due to chances for toxicity.

Vitamin C and iron are not considered as essential vitamins to be taken during pregnancy.

Normal labour is characterized by spontaneous onset, rhythmical uterine contractions along with vertex presentation. Cervical dilatation starts from the 1st stage of labour and intensity of the uterine contractions increases with passing time. Bleeding occurs after the child is expelled and the average loss is about 250-500 ml in a normal vaginal delivery.

Multiple pregnancy is considered a high risk for obstetric complications such as spontaneous abortion, hypertensive disorders, placenta previa, and fetal malformations. Specifically, the incidence of hypertensive disorders, a common source of maternal morbidity, is 15% to 35% in twin pregnancies, which is two to five times higher than in singleton pregnancies. Additionally, the aetiology of preterm birth is not completely understood, but the association between multiple pregnancy and preterm birth is well known. A secondary analysis of the WHO Global Survey dataset indicated that 35.2% of multiple births were preterm (< 37 weeks gestation); of all multiple births, 6.1% of births were before 32 weeks gestation, 5.8% were during weeks 32 and 33, and 23.2% were during weeks 34 through 37

Pre-eclampsia presents with other features in addition to the presence of hypertension, also it’s diagnosis cannot be made considered peripheral edema as the only presenting symptom. Proteinuria occurs more commonly in pre-eclampsia than in gestational hypertension and the latter is mostly asymptomatic.

Hypertensive disorders are found to complicate about 10% of all pregnancies. Common one among them is Gestational hypertension, which is defined as the new onset of hypertension after 20 weeks of gestation without any maternal or fetal features of pre-eclampsia, in this case BP will return to normal within three months of postpartum.

Types of hypertensive disorders during pregnancy:
1. Pregnancy-induced hypertension:
a. Systolic blood pressure (SBP) above 140 mm of Hg and diastolic hypertension above 90 mmHg occurring for the first time after the 20th week of pregnancy, which regresses postpartum.
b. The rise in systolic blood pressure above 25 mm of Hg or diastolic blood pressure above 15 mm of Hg from readings before pregnancy or in the first trimester.
2. Mild pre-eclampsia:
BP up to 170/110 mm of Hg in the absence of associated features.
3. Severe pre-eclampsia:
BP above 170/110 mm of Hg and along with features such as kidney impairment, thrombocytopenia, abnormal liver transaminase levels, persistent headache, epigastric tenderness or fetal compromise.
4. Essential (coincidental) hypertension:
Chronic underlying hypertension occurring before the onset of pregnancy or persisting after postpartum.
5. Pregnancy-aggravated hypertension:
Underlying hypertension which is worsened by pregnancy.

To diagnose pre-eclampsia clinically, presence of one or more of the following symptoms are required along with a history of onset of hypertension after 20 weeks of gestation.
– Proteinuria: Above 300 mg/24 h or urine protein
reatinine ratio more than 30 mg/mmol.
– Renal insufficiency: serum/plasma creatinine above 0.09 mmol/L or oliguria.
– Liver disease: raised serum transaminases and severe epigastric or right upper quadrant pain.
– Neurological problems: convulsions (eclampsia); hyperreflexia with clonus; severe headaches with hyperreflexia; persistent visual disturbances (scotomata).
– Haematological disturbances like thrombocytopenia; disseminated intravascular coagulation; hemolysis.

Predisposing factors of preterm delivery include a short cervix (or if it shortens earlier than in the third trimester), urinary tract or sexually transmitted infections, open cervical os, and history of a previous premature delivery. Increased uterine size can also contribute to preterm delivery and is seen with cases of polyhydramnios, macrosomia and multiple pregnancies. The shorter the cervical length, the greater the risk of a premature birth.
In this case, the risk of bacterial vaginosis and candidiasis contributing to preterm delivery would be lower than if in the context of an open cervical os. However, the risk of premature delivery is significantly increased if it is found that the fetal fibronectin test is positive, even if the os is closed.

Oesophageal atresia of the foetus interrupts the normal circulation of the amniotic fluid. This causes polyhydramnios and subsequent distension of the uterus impacting proper expansion of the lungs. This would explain the difficulty breathing.

These are the six routine blood tests that every mum-to-be has to undergo around week 7 of pregnancy: Full Blood Count, Blood Typing, Hepatitis B Screening, Syphilis Screening, HIV Screening and Oral Glucose Tolerance Test (OGTT)

First stage of the labour starts with the contractions of the uterus. With time, the no. of contractions, its duration and intensity increases. It ends once the cervix is fully dilated.

Presentation in the given case is classic for premature rupture of membranes (PROM) which was probably caused due to trauma during intercourse.
Premature rupture of membrane (PROM) is defined as the rupture of embryonic membranes before the onset of labor, regardless of the age of pregnancy. If occured before 37 weeks of gestation, it is termed as preterm PROM (PPROM.)

A sudden gush of watery fluid per vagina is the classic presentation of rupture of the membranes (ROM), regardless of gestational age, however nowadays many women presents with continuous or intermittent leakage of fluid or a sensation of wetness within the vagina or on the perineum. Presence of liquor flowing from the cervical os or its pooling in the posterior vaginal fornix are considered as the pathognomonic symptom of ROM. Assessment of fetal well-being, the position of the fetus, placental location, estimated fetal weight and presence of any anomalies in PROM and PPROM are done with ultrasonographic studies.

Retained semen will not result in the findings mentioned in this clinical scenario as it have a different appearance.

Infections will not be a cause for this presentation as it will be associated with characteristic features like purulent cervical discharge, malodorous vaginal discharge, etc. Pooling of clear fluid in the posterior fornix is pathognomonic for ROM.

Urine leakage is common during the pregnancy, but it is not similar to the clinical scenario mentioned above.

Absence of findings like cervical dilation and bulging membranes on speculum exam makes cervical insufficiency an unlikely diagnosis in this case.

All of the conditions that comprise fetal alcohol spectrum disorders stem from one common cause, which is prenatal exposure to alcohol. Alcohol is extremely teratogenic to a foetus. Its effects are wide-ranging and irreversible. Although higher amounts of prenatal alcohol exposure have been linked to increased incidence and severity of fetal alcohol spectrum disorders, there are no studies that demonstrate a safe amount of alcohol that can be consumed during pregnancy. There is also no safe time during pregnancy in which alcohol can be consumed without risk to the foetus. Alcohol is teratogenic during all three trimesters. In summary, any amount of alcohol consumed at any point during pregnancy has the potential cause of irreversible damage that can lead to a fetal alcohol spectrum disorder.

In general, diagnoses within fetal alcohol spectrum disorders have one or more of the following features: abnormal facies, central nervous system abnormalities, and growth retardation.

According to the laboratory reports, patient has developed urinary tract infection and should be treated with one week course of oral antibiotics.
As the patient is pregnant, antibiotics like cephalexin, co-amoxiclav and nitrofurantoin must be considered as these are safe during pregnancy.

Due to this Patient’s allergic history to penicillin, cephalexin can be considered as the best option. Risk of cross allergy would have been higher if the patient had any history of anaphylactic reactions to penicillin.

In Australia, Amoxicillin is not recommended to treat UTI due to resistance.Tetracyclines also should be avoided during pregnancy due to its teratogenic property.

There is an association between 20 to 30% increase in the risk for developing pyelonephritis during later pregnancy and untreated cases of bacteriuria in pregnancy. This is due to the physiological changes occurring to urinary tract during pregnancy, it is also found that untreated bacteriuria can be associated with even preterm birth and low birth weight. Risk of symptomatic urinary tract infection (UTI) during pregnancy can be reduced by antibiotic treatment of asymptomatic bacteriuria

The most common pathogen associated with asymptomatic bacteriuria is Escherichia coli, which accounts to more than 80% of isolates and the second most frequently cultured uropathogen is Staphylococcus saprophyticus. Other Gram-positive cocci, like group B streptococci, are less common. Gram-negative bacteria such as Klebsiella, Proteus or other Enterobacteriaceae are the other organisms involved in asymptomatic bacteriuria.

Although the context patient is asymptomatic, her urine dipstick shows positive nitrite and leukocyte, suggestive of urinary tract infection, so oral antibiotics like cephalexin or nitrofurantoin are advisable. Normally a five day course of oral antibiotic will be sufficient for the treatment of uncomplicated UTI or asymptomatic bacteraemia in pregnant women. As the patient is currently at her 38 weeks of gestation nitrofurantoin is contraindicated so it is best to prescribe her with Oral Cephalexin. This is because nitrofurantoin is associated with an increased risk of neonatal jaundice and haemolytic anaemia, so should not be used close to delivery, that is after 37 weeks of gestation or sooner if early delivery is planned.

Acute pyelonephritis should be treated with Intravenous antibiotic treatment, guided by urine culture and sensitivity reports as soon a available. A course of minimum of 10-14 days with IV + oral antibiotics is recommended as treatment for pyelonephritis, along with an increased fluid intake as intravenous fluids in clinically dehydrated patients. Even though urinary alkalisers are safe in pregnancy, prescription of urinary alkalisers alone is not recommended due to its low effectiveness compared to antibiotics, also as it can result in a loss of treatment efficacy urinary alkalisers should never be used in combination with nitrofurantoin.

At any stage of pregnancy, if Streptococcus agalactiae, a group B streptococcus [GBS], is detected in urine the intrapartum prophylaxis for GBS is usually indicated.

The best next line of management is to administer an oxytocic (Syntocinon) infusion.

This is because the progress of labour is slow, and it necessary to augment it. As the membranes have already ruptured, the next step is to increase the contractions and induce labour using an infusion of oxytocic (Syntocinon) infusion.

Extra fluid is also required, but this will be administered alongside the Syntocinon infusion.

A lumbar epidural block is indicated in patients with an occipito-posterior (OP) position. This should not be attempted until more pain relief is required and the progress of labour is reassessed.

A Caesarean section may be necessary due to obstructed labour or fetal distress, it is not indicated at this stage.

Taking blood and holding it in case cross-matching is ultimately required is common, but most patients do not have blood cross-matched prophylactically in case there is a need to be delivered by Caesarean section and require a transfusion.

Gas gangrene is synonymous with myonecrosis and is a highly lethal infection of deep soft tissue, caused by Clostridium species, with Clostridium perfringens being the most common. This organism has also had increased incidence as the cause of deep tissue infections associated with childbirth and infections after gynaecologic procedures including septic abortions, which can cause gas gangrene of the uterus.
Health care workers should suspect gas gangrene if anaerobic gram-positive bacilli are present in a wound with necrosis of soft tissue and muscle. The organisms produce a gas identifiable on x-ray or CT scans.
Patients with gas gangrene (myonecrosis) present with signs of infection such as fever, chills, pain, and less superficial inflammation at the site of infection than one would expect given the deep penetrating nature of these infections. The condition of the patient can rapidly progress to sepsis and death if not treated aggressively. The wound discharge is often dishwater looking with a musty order.

This patient at 36 weeks of gestation likely had a generalized tonic-clonic seizure. A new-onset seizures in pregnancy can be due to either due to eclampsia which is pregnancy-specific or due to other non-obstetric causes like meningitis, intracranial bleeding etc.

In pregnant and postpartum women eclampsia is the most common cause for seizures which is classically associated with preeclampsia, a new-onset hypertension at ≥20 weeks gestation, with proteinuria and/or signs of end-organ damage. Although this patient has hypertension, absence of proteinuria and the additional findings like agitation, dilated pupils, hyponatremia and normal head CT scan are suggestive of another etiology. Patients with eclampsia will show white matter edema in head CT scan.

Amphetamine intoxication, which causes overstimulation of the alpha-adrenergic receptors resulting in tachycardia, hypertension and occasional hyperthermia, might be the cause for this patient’s seizures. Some patients will also have diaphoresis and minimally reactive, dilated pupils and severe intoxication can lead to electrolyte abnormalities, including significant hyponatremia (possibly serotonin-mediated) and resultant seizure activity.
Confirmation of Amphetamine intoxication can be done by a urine drug testing. it is essential to distinguishing between eclampsia and other causes of seizure in this case, as it will help to determine whether or not there is need for an emergency delivery.

Altered mental status and electrolyte abnormalities can be due to heat stroke, however, patients affected this way will have an elevated temperature of >40 C /104 F associated with hemodynamic instabilities like hypotension.

Hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome is a hypertensive disorder of pregnancy which can result in seizures (ie, eclampsia), but this patient’s hematocrit level is normal without any hemolysis, also patients with HELLP syndrome typically presents with a platelet count <100,000/mm3. Seizures and altered mental status in patients with prior splenectomy can be due to pneumococcal meningitis however, such patients will present with high fever and nuchal rigidity, making this diagnosis less likely in the given case. Amphetamine intoxication can present with hypertension, agitation, diaphoresis, dilated pupils, and a generalized tonic-clonic seizure due to hyponatremia, which is most likely to be the case here.

This infant will most likely be diagnosed as having fetal hydantoin syndrome, which occurs due to an in utero exposure to antiepileptic drugs like phenytoin, carbamazepine, valproate etc. 

Multiple antiepileptics, due to their ability to cross placenta, have teratogenic effects which will result in low folate and high oxidative metabolite levels in the fetus. This likely combined effect results deformities like cleft lip and palate, wide anterior fontanelle, distal phalangeal hypoplasia and cardiac anomalies like pulmonary stenosis, aortic stenosis etc in the fetus. There will be developmental delay and poor cognitive outcomes as a result of neural tube defects and microcephaly associated with this. Therefore, prior to conception, those patients who require antiepileptics for seizure control during pregnancy should titrate it to the lowest dose and must started on high-dose (4 mg) folic acid supplementation to minimize the risk of such congenital malformations.

Fetal alcohol syndrome commonly presents with microcephaly and midfacial hypoplasia, but is not association with cleft lip or palate.

Cocaine use during pregnancy can be associated with preterm delivery, abruptio placentae and fetal growth restriction; but there is no evidence to prove its association with congenital defects.

Fetal renal failure with associated oligohydramnios that results in pulmonary hypoplasia, growth restriction, and limb defects are the complications associated with the use of lisinopril and other angiotensin-converting enzyme inhibitors during pregnancy; but it does not cause cleft lip or palate.

Most infants with congenital syphilis are asymptomatic at birth and those with symptoms typically have rhinitis or “snuffles, hepatomegaly and a maculopapular rash none of which are seen in this patient.

Fetal hydantoin syndrome results from the in-utero exposure to antiepileptic drugs like phenytoin, carbamazepine etc and is usually presented with microcephaly, a wide anterior fontanelle, cleft lip and palate, and distal phalangeal hypoplasia.

Pulmonary hypertension (PH) is an increase of blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, leading to shortness of breath, dizziness, fainting, and other symptoms, all of which are exacerbated by exertion. PH in pregnancy carries a 25–56% maternal mortality rate with a mixture of intrapartum and postpartum deaths.

Current recommendations for management of PH in pregnancy include termination of pregnancy if diagnosed early, or utilizing a controlled interventional approach with early nebulized prostanoid therapy and early elective caesarean section under regional anaesthesia. Other recommended therapies for peripartum management of PH include sildenafil and nitric oxide.