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The first widely recognized modern cancer-chemotherapy drug was nitrogen mustard, later known as mechlorethamine or mustine. It was closely related to mustard gas—but an important distinction is often lost:

• Sulfur
  mustard
  was the blistering chemical weapon used during World War I.
• Nitrogen
  mustard
  was a related family of laboratory-made compounds initially investigated
  for chemical warfare.
• Researchers
  discovered that these chemicals attacked blood-forming and lymphatic
  tissues. That destructive property was redirected against cancer.

1. Mustard gas revealed an unusual biological effect

Germany first used sulfur mustard extensively as a chemical weapon in 1917. Besides causing terrible burns, blindness, and lung injuries, doctors studying exposed soldiers found severe damage to:

• Bone
  marrow
• Lymph
  nodes and other lymphatic tissue
• White
  blood cells
• Cells
  lining the digestive tract

Sulfur mustard was especially damaging to cells that were actively reproducing. This suggested an important possibility: perhaps a related chemical could destroy cancers made from rapidly multiplying white blood cells, including leukemia and lymphoma.

2. Scientists developed nitrogen mustards

During the 1930s, chemists produced compounds called nitrogen mustards by replacing the sulfur atom in sulfur mustard with nitrogen-containing chemical groups.

Therefore, the first cancer drug was not simply battlefield mustard gas packaged as medicine. It was a chemically related compound developed during chemical-warfare research.

Like sulfur mustard, nitrogen mustards contain reactive chemical groups capable of attaching themselves to cellular molecules. Some nitrogen mustards were found to have particularly strong effects throughout the body—especially against bone marrow and lymphatic cells.

3. Secret wartime research moved the discovery forward

During World War II, the U.S. government asked researchers to study possible chemical-warfare agents and treatments for exposure.

At Yale University, pharmacologists Louis S. Goodman and Alfred Gilman investigated sulfur and nitrogen mustards. Their research group also included:

• Frederick
  S. Philips,
  a pharmacologist
• Thomas
  Dougherty,
  an anatomist
• Roberta
  Allen,
  a researcher
• Gustaf
  Lindskog,
  the surgeon who helped move the drug into patient treatment

Because the work was classified, nitrogen mustard was reportedly identified in records simply as “Substance X.”

When the researchers gave nitrogen mustard to mice with transplanted lymphomas, the tumors shrank dramatically. Unfortunately, the drug also suppressed the animals’ bone marrow, and the cancers eventually returned. Nevertheless, the experiments showed that a chemical carried through the bloodstream could attack cancer throughout the body.

4. The first patient

In 1942, the Yale team selected a 47-year-old factory worker identified in the records as J.D. He had advanced lymphosarcoma—what would now be classified as a form of non-Hodgkin lymphoma.

His tumors were extensive, and radiation had stopped working. He reportedly could barely move his head because of the masses around his neck.

On August 27, 1942, J.D. received an intravenous dose of nitrogen mustard. Some historical accounts give December 1942 as the beginning of the formal clinical trial, but Yale’s recovered patient record places the first administration in August.

The result was remarkable:

• His
  tumors softened within days.
• The
  masses became much smaller.
• His
  pain and mobility improved.
• For
  a short time, doctors could no longer detect some of the tumors
  clinically.

But the improvement was temporary. Nitrogen mustard also severely damaged his bone marrow, causing his white-cell count to fall. The cancer developed resistance and returned. J.D. died on December 1, 1942.

The first small Yale series ultimately included six patients. The treatment produced striking but temporary tumor regressions rather than permanent cures.

5. Where the Bari mustard-gas disaster fits

The December 2, 1943, German air raid on Bari, Italy, is frequently described as the event that created chemotherapy—but that is not completely accurate.

The American Liberty ship SS John Harvey was secretly carrying sulfur-mustard bombs. During the attack, the ship exploded and released mustard agent into the harbor. Servicemen and civilians were exposed through contaminated water, oil, and vapor.

Lieutenant Colonel Stewart F. Alexander, an American physician and chemical-warfare specialist, examined the casualties. Autopsies and blood tests revealed profound suppression of white blood cells and destruction of bone marrow and lymphatic tissue.

Those findings provided powerful human evidence that mustard compounds attacked blood-forming cells. However, Yale’s first nitrogen-mustard cancer treatment had already occurred in 1942, more than a year before Bari. Therefore, Bari reinforced and expanded knowledge of mustard’s biological effects; it did not initiate the first Yale treatment.

6. Why the discovery remained secret

The research involved classified chemical-warfare information. The United States did not want enemy governments to know:

• That
  it possessed mustard weapons
• Where
  those weapons were being transported
• What
  American scientists had learned about them
• That
  nitrogen mustards were being studied medically

Consequently, Goodman, Gilman and their colleagues could not publish the clinical findings immediately. Their landmark report, “Nitrogen Mustard Therapy,” appeared in The Journal of the American Medical Association on September 21, 1946.

7. How nitrogen mustard kills cancer cells

Nitrogen mustard belongs to a class of drugs called alkylating agents.

Inside a cell, the molecule forms highly reactive structures that bind to DNA. It can create cross-links, including connections between the two strands of the DNA double helix. The damaged DNA becomes difficult or impossible to copy correctly.

A cell preparing to divide may then:

• Stop
  dividing
• Accumulate
  lethal genetic damage
• Trigger
  its internal cell-death process
• Die
  while attempting to reproduce

Cancer cells often divide rapidly, making them particularly vulnerable. But nitrogen mustard cannot perfectly distinguish cancer cells from healthy fast-growing cells. It can therefore also damage:

• Bone
  marrow
• Hair
  follicles
• Digestive-tract
  lining
• Reproductive
  cells

That explains both its anticancer effects and many traditional chemotherapy side effects.

8. What the first treatment accomplished

Nitrogen mustard usually did not permanently cure the early lymphoma patients. Its historic importance was that it demonstrated, for the first time in a convincing clinical setting, that a medicine traveling through the bloodstream could cause a widespread cancer to regress.

It became the prototype for later alkylating chemotherapy drugs, including:

• Cyclophosphamide
• Ifosfamide
• Chlorambucil
• Melphalan
• Bendamustine

Mechlorethamine itself has continued to be used in certain lymphoma treatments, although modern formulations and treatment combinations are far more controlled than the original experiments.

The central connection

The historical pathway was:

In short, the first modern cancer chemotherapy emerged directly from chemical-warfare research. A substance designed to injure and kill was chemically modified and medically redirected so that its cell-killing ability could be used against cancer. The connection to mustard gas is therefore real and fundamental—but the administered drug was a related nitrogen mustard, not ordinary sulfur mustard taken directly from a battlefield weapon.

Yes. Doctors know that chemotherapy can kill patients. That fact should never be minimized or concealed.

Chemotherapy is deliberately toxic: it is intended to kill cancer cells, but it can also kill healthy cells and occasionally the patient. The medical question is whether the expected danger from the cancer is greater than the danger from treatment.

How chemotherapy can cause death

Fatal complications can include:

• Severe
  bone-marrow suppression
• Overwhelming
  infection or sepsis after white blood cells collapse
• Uncontrolled
  bleeding from low platelets
• Heart,
  liver, kidney or lung damage
• Dangerous
  blood clots
• Severe
  allergic reactions
• Tumor-lysis
  syndrome
• Secondary
  leukemia or another later cancer
• Treatment
  mistakes or excessive dosing

The CDC explicitly warns that infection during chemotherapy can result in hospitalization or death and that fever during treatment may be a medical emergency.

The FDA’s historical label for intravenous mechlorethamine—Mustargen, the original nitrogen-mustard drug—described it as “HIGHLY TOXIC” and a powerful blistering agent.

Does chemotherapy also save lives?

Yes. The danger does not mean chemotherapy never works.

Depending on the cancer, chemotherapy may:

• Cure
  it
• Reduce
  the chance of recurrence after surgery
• Shrink
  it before surgery
• Extend
  life
• Relieve
  pain or obstruction without offering a cure

Chemotherapy has contributed to high cure rates for several leukemias, lymphomas, testicular cancer and some childhood cancers. But benefits vary enormously. A regimen that offers a strong chance of curing one cancer may give another patient only a small possibility of living a few months longer.

Therefore, saying either “chemotherapy always saves people” or “chemotherapy only kills people” would be false. It can do both, and the balance depends on the drug, dosage, cancer, stage, age and health of the patient.

What was troubling about the first treatment?

The first nitrogen-mustard experiment arose from a classified military chemical-warfare program. The drug was extremely toxic, its proper dosage was uncertain, and its effects in humans were poorly understood.

The first Yale patient experienced dramatic tumor shrinkage, followed by profound bone-marrow suppression, recurrence and death. The treatment did not cure him. It proved that a bloodstream-delivered chemical could temporarily destroy lymphoma, while simultaneously demonstrating that it could injure the patient severely.

The original experiments also occurred before today’s institutional review boards, detailed consent forms and modern human-subject protections. Historical sources say the patient agreed after risks were explained, but that should not be confused with the documentation and independent oversight expected today.

The Bari qualification is important

The Bari disaster was not the original discovery that mustard compounds suppressed blood cells. Doctors had observed blood and bone-marrow damage after World War I exposure, and Yale treated its first patient in 1942.

Bari occurred in December 1943. It supplied further human evidence after large numbers of servicemen and civilians were accidentally exposed to sulfur mustard. So the truthful sequence is:

1. World War I exposures revealed damage to blood-forming tissue.

2. Nitrogen-mustard chemical-warfare compounds were developed and studied.

3. Yale animal experiments showed lymphoma regression.

4. A patient received nitrogen mustard in 1942.

5. The Bari disaster in 1943 reinforced evidence of marrow and lymphatic destruction.

6. Classified results were publicly published in 1946.

What patients deserve to be told

Before treatment, an oncologist should explain:

• Whether
  the objective is cure, longer survival or symptom relief
• The
  chance of receiving that benefit
• The
  chance of serious or fatal toxicity
• The
  likely outcome without chemotherapy
• Alternatives,
  including surgery, radiation, targeted therapy, immunotherapy, hormonal
  treatment, a clinical trial or supportive care
• Whether
  dose reduction or no treatment is reasonable

The most revealing question is not merely, “Does chemotherapy work?” It is:

“Out of 100 patients like me, how many live longer because of this treatment, by how much, and how many experience severe or fatal complications?”

A patient may also request a second opinion from an independent oncologist. That is especially reasonable when the expected benefit is small or the stated purpose of treatment is unclear.

One urgent safety point: a person receiving chemotherapy who develops a fever—often 100.4°F/38°C or higher, depending on the oncology team’s instructions—should contact the cancer-treatment team immediately. Infection during chemotherapy can become fatal rapidly.

The SS John Harvey Mustard-Gas Disaster at Bari

The destruction of the American Liberty ship SS John Harvey during the German air raid on Bari, Italy, on December 2, 1943, produced one of the deadliest accidental chemical-weapons releases of World War II. It also gave military physicians an unusually detailed—and tragic—opportunity to observe how sulfur mustard attacks the blood, bone marrow, immune system, skin, lungs, and gastrointestinal tract.

Why mustard bombs were aboard the ship

By late 1943, Allied leaders feared that Germany might use chemical weapons to stop the Allied advance through Italy. The United States therefore secretly transported sulfur mustard to the Mediterranean for retaliatory use if Germany attacked first with poison gas.

The John Harvey carried approximately:

• 2,000
  M47A1 chemical bombs
• Each
  bomb weighed approximately 100 pounds
• Each
  contained roughly 60–70 pounds of liquid sulfur mustard
• The
  entire shipment represented about 100 tons of chemical bombs

The bombs were not intended for an Allied first strike. They were a concealed retaliatory reserve. Only a small number of officers knew the true nature of the cargo, and the ship was waiting for instructions and a secure place to unload it.

An important technical correction is that “mustard gas” is somewhat misleading. Sulfur mustard is an oily liquid at ordinary temperatures. It can evaporate slowly into a poisonous vapor or be dispersed as droplets and aerosols, but it was stored aboard the ship principally as a liquid.

The German attack on Bari

Bari was a critically important Allied supply port. On the evening of December 2, German reconnaissance and planning caught the harbor dangerously congested and inadequately protected.

More than 100 German Junkers Ju 88 bombers attacked the port. Bombs struck ships loaded with ammunition, fuel, and other supplies, creating a chain of explosions and fires. Approximately 28 Allied merchant vessels were sunk or destroyed, including five American Liberty ships.

A bomb struck the John Harvey. Its conventional ammunition began exploding, and the fire eventually reached the secret chemical cargo. The resulting explosion destroyed the ship and killed everyone known to be aboard—including its merchant crew, Navy Armed Guard personnel, and Army chemical specialists who understood the cargo. The Naval History and Heritage Command records 36 crewmen, 20 Navy Armed Guards, and 10 U.S. soldiers killed aboard the ship.

Because the people who knew what the vessel carried were dead, rescuers and hospital personnel initially received no warning that they were dealing with chemical casualties.

How the mustard spread through the harbor

Some bombs exploded immediately. Others were ruptured or thrown into the water. Their sulfur mustard entered a harbor already covered with fuel oil from burning and damaged ships.

That created several routes of exposure.

1. Mustard dissolved in the harbor’s oil

Sulfur mustard does not dissolve readily in water, but it mixes much more effectively with oils and organic liquids. Fuel oil therefore acted as a carrier.

Sailors who jumped or were blown into the harbor became coated with a mixture of:

• Seawater
• Bunker
  fuel and petroleum
• Liquid
  sulfur mustard
• Burning
  debris and chemical residue

The contaminated oil adhered to their skin and clothing. Because mustard can penetrate clothing and intact skin, prolonged contact allowed substantial quantities to enter their bodies.

This helps explain why many men later developed severe systemic poisoning even when they had not initially appeared badly burned.

2. Contaminated clothing prolonged exposure

Rescued men were wet, cold, injured, and covered with oil. Hospitals were overwhelmed, and some casualties remained in their contaminated clothing for hours.

Medical workers initially treated them as ordinary bombing, immersion, or burn victims. Because nobody warned the doctors about mustard, clothing was not always removed immediately, and victims were not promptly washed with uncontaminated water.

The continuing contact gave the chemical additional time to penetrate their skin. The Navy’s historical account concludes that some deaths might have been prevented by prompt removal of contaminated clothing and washing with fresh water.

3. Mustard vapor drifted over Bari

Heat from the fires caused part of the released liquid to evaporate. Explosions also dispersed mustard as droplets and aerosols. A contaminated cloud moved over sections of the harbor and city.

Consequently, exposure was not limited to men who fell into the water. It included:

• Ship
  crews
• Harbor
  workers
• Firefighters
  and rescue personnel
• Medical
  workers handling contaminated casualties
• Italian
  civilians living near the port

The National Academies’ historical assessment reports that hundreds of civilians arrived for treatment after a mustard cloud moved across parts of the city.

Why the injuries were initially mysterious

Mustard poisoning frequently has a latent period. A person can feel relatively well immediately after exposure and then deteriorate several hours later.

Early signs among the Bari victims included:

• Eye
  irritation progressing to swollen eyelids and temporary blindness
• Redness
  followed by painful skin blistering
• Nausea
  and vomiting
• Hoarseness,
  coughing, and respiratory distress
• Severe
  genital and groin burns, because warm, moist areas are particularly
  vulnerable
• Fever
  and diarrhea
• Falling
  white-blood-cell counts
• Secondary
  infections and pneumonia

Many sailors had been pulled from cold water and appeared to have ordinary fuel-oil irritation, burns, shock, or hypothermia. Their mustard injuries did not necessarily resemble the classic battlefield cases seen during World War I.

This was partly because the Bari victims had experienced a particularly dangerous combination: mustard dissolved in oily water, held against the body by soaked clothing, with simultaneous inhalation of vapor and smoke.

Stewart F. Alexander’s investigation

Who he was

Lieutenant Colonel Stewart Francis Alexander was a U.S. Army physician attached to the medical staff of the Allied command in the Mediterranean. He had received specialized training in chemical-warfare medicine at Edgewood Arsenal, Maryland.

When military authorities learned of the unexplained blistering, blindness, and rapidly deteriorating patients, Alexander was sent from Allied headquarters in Algiers to Bari.

The clues he followed

Alexander was initially not given a straightforward confirmation that mustard weapons were present. Nevertheless, several clues pointed toward sulfur mustard:

• Delayed
  eye and skin injuries
• Large
  blisters in warm and moist areas of the body
• Respiratory
  damage inconsistent with ordinary smoke exposure
• A
  garlic-like odor reported around some casualties
• Serious
  injuries among men who had been immersed in oily harbor water
• A
  geographical concentration of severe cases around the destroyed John
  Harvey
• Unexplained
  reductions in white blood cells

Alexander reconstructed where the patients had been at the time of the raid. That investigation led him toward the John Harvey as the center of the chemical contamination.

Investigators also recovered a fragment from an American M47A1 chemical bomb. The combination of the bomb fragment, patient distribution, symptoms, blood findings, and autopsies established that sulfur mustard was responsible.

What the blood tests revealed

Alexander ordered repeated blood counts instead of looking only at visible burns. Those tests demonstrated that the chemical had produced a severe systemic effect.

Some patients initially developed an increase in circulating white cells as their bodies reacted to injury. This was followed by a dangerous decline:

• Leukopenia: abnormally low
  white-blood-cell levels
• Lymphopenia: depletion of
  lymphocytes, important immune cells
• Thrombocytopenia: reduced
  platelets, increasing the risk of bleeding
• In
  the most severe cases, pancytopenia: depletion of white cells,
  red-cell precursors, and platelets because the marrow could no longer
  produce them normally

The lowest blood counts often occurred several days after exposure. This delayed pattern meant that a casualty who initially appeared likely to survive could suddenly become critically ill.

With too few white blood cells, patients became highly vulnerable to bacterial infection. With too few platelets, they could develop abnormal bleeding. Damage to the intestinal lining allowed bacteria to cross into the bloodstream more easily.

Consequently, mustard casualties did not necessarily die from their skin burns alone. They could die days later from:

• Pneumonia
• Sepsis
• Respiratory-tract
  destruction
• Gastrointestinal
  injury and fluid loss
• Hemorrhage
• Combined
  bone-marrow and immune-system failure

What the autopsies showed

Alexander’s published medical report drew on 53 autopsies, together with clinical histories and blood studies.

The examinations revealed that sulfur mustard was not simply a blistering agent. It behaved as a systemic cellular poison.

Bone marrow

Normally active bone marrow contains large numbers of immature cells developing into white cells, red cells, and platelets. In severe mustard casualties, the marrow became markedly depleted or hypoplastic.

The tissue was failing to replace the circulating cells that the body needed. Alexander connected the degree of marrow hypoplasia with the leukopenia and thrombocytopenia observed before death. The pattern indicated direct chemical injury rather than merely an indirect response to infection.

Lymph nodes and spleen

Lymphocytes reproduce rapidly in lymph nodes, the spleen, and other lymphatic tissues. Mustard exposure destroyed many of these cells.

Among the 53 autopsies:

• 33
  spleens—about 62 percent—showed gross abnormalities
• Many
  spleens appeared small, pale, or shrunken
• Lymph
  nodes displayed abnormal discoloration
• Microscopic
  examinations found injured and fragmenting lymphocytes in some tissues

These findings demonstrated profound damage to the immune and lymphatic systems.

Gastrointestinal tract

The lining of the mouth, esophagus, stomach, and intestines renews itself rapidly. It was therefore vulnerable to the same cell-killing effect.

Autopsies found areas of epithelial injury, ulceration, hemorrhage, and tissue death. This damage helps explain the nausea, vomiting, diarrhea, dehydration, bleeding, and infection seen in severely poisoned patients.

Respiratory system

Victims who inhaled vapor, smoke, or contaminated aerosols developed inflammation and destruction along the respiratory tract:

• Swollen
  airway tissue
• Ulceration
• Sloughing
  of damaged airway lining
• Bronchitis
• Bronchopneumonia
• Secondary
  bacterial infection

As injured cells detached, dead tissue and secretions could obstruct the airways. Pneumonia became especially dangerous once the same patients’ white-cell defenses had collapsed.

Skin and eyes

Mustard chemically injured the skin’s dividing basal cells. The surface might initially look only red, but the damaged layers later separated and produced large blisters.

The eyes were extremely sensitive. Exposure could cause:

• Severe
  conjunctivitis
• Swollen
  eyelids
• Corneal
  injury
• Intense
  pain and light sensitivity
• Temporary
  blindness

Some rescued sailors carried enough contamination aboard rescue ships that members of those ships’ crews subsequently developed eye and respiratory injuries. The National Academies records one destroyer’s officers and crew becoming blinded after rescuing contaminated men from the harbor.

Alexander’s most important conclusion

Alexander concluded that sulfur mustard preferentially injured tissues in which cells were actively dividing. These included:

• Bone
  marrow
• Lymphatic
  tissue
• Gastrointestinal
  lining
• Skin-generating
  layers
• Respiratory
  epithelium

This was medically significant because cancers such as lymphoma and leukemia also involve rapidly proliferating cells. The central therapeutic idea was therefore:

If a related chemical could be administered in a controlled dose, perhaps it could suppress malignant lymphoid cells more severely than it injured the patient’s recoverable normal tissues.

That principle became fundamental to cytotoxic chemotherapy: damage the cancer enough to produce regression while allowing essential normal tissues—particularly bone marrow—to recover.

The important correction about Bari and chemotherapy

It is frequently said that the Bari disaster “caused the discovery of chemotherapy.” That is an oversimplification.

The timeline shows that researchers were already investigating mustard compounds before Bari:

1. Physicians treating World War I mustard casualties had reported suppression of white blood cells and marrow activity as early as 1919.

2. During World War II, Louis Goodman, Alfred Gilman, Frederick Philips, Thomas Dougherty, and colleagues at Yale studied nitrogen mustards under a secret military contract.

3. They produced tumor regression in laboratory animals.

4. In December 1942—approximately one year before Bari—a Yale team treated a patient with lymphosarcoma using a nitrogen-mustard compound. The tumors temporarily regressed.

5. The Bari disaster occurred in December 1943 and provided a large, well-documented human example of mustard’s powerful effects on marrow and lymphatic tissue.

Therefore, Bari did not initiate the first nitrogen-mustard cancer trial. Alexander’s findings confirmed and strengthened the biological rationale, supplied unusually extensive human pathological evidence, and helped stimulate or support further investigation once wartime secrecy eased.

The chemotherapy drugs were based primarily on nitrogen mustard, not on administering the sulfur mustard released at Bari. Nitrogen mustards are chemically related agents whose properties could be adapted more practically for systemic medical treatment.

Secrecy and its consequences

The cargo was secret because Allied leaders did not want Germany to believe that the Allies intended to initiate chemical warfare. Revealing the cargo also could have exposed Allied chemical-weapons preparations and possibly encouraged German retaliation.

That secrecy, however, came at a terrible medical cost:

• Harbor
  authorities and doctors were not promptly informed.
• Patients
  were initially left in contaminated clothing.
• Contaminated
  patients endangered rescuers and hospital workers.
• Medical
  personnel did not immediately begin mustard-specific decontamination.
• Official
  casualty descriptions sometimes referred only to burns or enemy action.
• Alexander’s
  report and related records remained restricted.

The United States acknowledged the incident in a limited statement in February 1944, but American records were not fully declassified until 1959.

How many people were poisoned or killed?

The most defensible documented figures are:

• At
  least 628 military patients and medical personnel developed
  chemical-poisoning symptoms.
• At
  least 83 of those recognized military mustard casualties died by
  the end of December.
• Approximately
  90 percent of the identified gas casualties were American merchant
  seamen.
• Civilian
  numbers remain uncertain because many residents fled Bari, received
  treatment outside the formal Allied system, or were never properly
  recorded.

Some later sources claim close to 1,000 civilian deaths, but this figure is less securely documented than the 628 military cases and 83 deaths recorded in Alexander’s medical series. It should therefore be presented as an estimate, not an established total.

The overall raid killed many people through conventional explosions, fires, collapsing structures, and sinking ships in addition to chemical exposure. That makes it difficult to separate with certainty:

• Immediate
  bombing deaths
• Mustard-related
  deaths
• Deaths
  caused by both burns and chemical poisoning
• Later
  civilian deaths never reported to Allied authorities

Historical importance

The Bari disaster demonstrated three things with exceptional clarity:

1. Sulfur mustard is more than a surface-burning weapon. Once absorbed, it can attack the entire blood-forming and immune system.

2. Chemical injuries may be delayed. People who initially appear stable can deteriorate sharply several days later.

3. The same cell-killing principle can be redirected therapeutically. Chemists and physicians adapted related nitrogen-mustard compounds to attack cancers of the lymphatic and blood-forming systems.

Nitrogen mustard did not cure the earliest patients permanently; tumors often returned as the bone marrow recovered. Nevertheless, those temporary regressions provided proof that a drug circulating through the body could shrink disseminated cancer. That was a foundational step toward modern combination chemotherapy.