263e: Radiation Terrorism

The threat of a terror attack employing nuclear or radiation-related devices is unequivocal in the twenty-first century. Such an attack would certainly have the potential to cause unique and devastating medical and psychological effects that would require prompt action by members of the medical community. This chapter outlines the most probable scenarios for an attack involving radiation as well as the medical principles for handling such threats.

Potential terrorist incidents with radiologic consequences may be considered in two major categories. The first is the use of radiologic dispersal devices. Such devices disseminate radioactive material purposefully and without nuclear detonation. An attack with a goal of radiologic dispersal could take place through use of conventional explosives with incorporated radionuclides (“dirty bombs”), one or more fixed nuclear facilities, or nuclear-powered surface vessels or submarines. Other means could include detonation of malfunctioning nuclear weapons with no nuclear yield (nuclear “duds”) and installation of radionuclides in food or water. The second and less probable scenario is the actual use of nuclear weapons. Each scenario poses its own specific medical threats, including “conventional” blast or thermal injury, introduction to a radiation field, and exposure to either external or internal contamination from a radioactive explosion.

Atomic isotopes with uneven numbers of protons and/or neutrons are typically unstable; such isotopes discharge particles or energy to matter as they move to stability, a process that is defined as radiation. Mass-containing particles, including alpha particles, electrons, and/or neutrons, may be transferred during this process (alpha radiation, beta radiation, and neutron radiation, respectively); alternatively, the transfer may consist only of energy in the form of a gamma ray. Alpha (α) radiation consists of heavy, positively charged particles, each of which contains two protons and two neutrons. Alpha particles usually are emitted from isotopes that have an atomic number of ≥82, such as uranium and plutonium. Due to their large size, alpha particles have limited penetrating power. Fine obstacles such as cloth and human skin usually can stop these particles from penetrating into the body. Thus they represent a small risk from external exposure. If they are somehow internalized, however, alpha particles can cause significant damage to human cells that are in their immediate proximity.

Beta (β) radiation consists of electrons, which are small, light, negatively charged particles (about 1/2000 the mass of a neutron or proton). Electrons can travel only a short, finite distance in tissue, with the precise distance depending on their energy. Exposure to beta particles is common in many radiation accidents. Radioactive iodine released in nuclear plant accidents is the best-known form of beta radiation. Plastic layers and clothing can stop most beta particles, and their penetration is generally measured at a few millimeters. A large quantum of energy delivered via beta particles to the basal stratum of the skin can cause a burn that is similar to a thermal burn and is treated as such.

Gamma (γ) rays and x-rays (both photons) are similar. Gamma rays are uncharged electromagnetic radiation discharged from a nucleus as a wave of energy. X-rays are the product of abrupt mechanical deceleration of electrons striking a heavy target such as tungsten. Although they are generated by different sources, gamma rays and x-rays have similar properties; that is, they have no charge and no mass, just energy. They travel easily through matter and thus are sometimes referred to as penetrating radiation. Gamma rays and x-rays are the principal types of radiation that cause dangerous total-body exposure. Gamma rays and x-rays of the same energy will cause the same biologic effects, and these effects will require the same treatment.

Neutron (η) particles are heavy and uncharged and are often emitted during nuclear detonation. They possess a wide energy range; their ability to penetrate tissues is variable, depending on their energy. They are less likely to be present in most scenarios of radiation bioterrorism than are the other forms of radiation discussed above.

Radiation interactions with atoms can result in ionization and the formation of free radicals that damage tissue by disrupting chemical bonds and molecular structures in the cell, including DNA. Protons, electrons, and gamma rays cause cellular damage through ionization of DNA. Depending on energy and other factors, some fraction of this damage will be caused by a direct strike to the DNA molecule (direct ionization). The remainder will be caused by ionization of water molecules to create free radicals that, in turn, damage DNA (indirect ionization). Ionization of DNA resulting from neutrons is exclusively indirect. Radiation damage can lead to cell death; the cells that recover may be mutated and at higher risk for subsequent cancer evolution. Cell sensitivity increases as the replication rate increases and cell differentiation decreases.

The commonly used units of radiation are the rad and the gray (Gy). The rad (radiation absorbed dose) is energy deposited within living matter and is equal to 100 ergs/g of tissue. The traditional rad has been replaced by the Système Internationale (SI) unit of the gray; 100 rad = 1 Gy, while 1 Gy is equal to 1 joule/kg. The sievert (Sv) is the SI unit that refers to the equivalent radiation dose in biologic tissues. While 1 Sv is equal to 1 joule/kg, Sv and Gy are not interchangeable units: Sv refers to the biologic effect of the radiation, while Gy refers to the physical energy being transferred.

Whole-body exposure occurs when radiation energy is deposited throughout the entire body. During a whole-body exposure, alpha and beta particles have limited penetration and do not cause significant noncutaneous injury unless emission results from an internalized source. Whole-body exposure from gamma rays, x-rays, or neutrons, which can penetrate through the body (the degree of which depends on their energy), can result in damage to multiple tissues and organs. The damage is proportional to the radiation exposure of the specific organ or tissue.

External contamination is a result of fallout of radioactive particles that land on the body surface, clothing, skin, and hair. This is the dominant element to consider in the mass-casualty situation resulting from a radioactive terrorist strike. The common contaminants primarily emit alpha and beta radiation. Alpha particles do not penetrate beyond the skin and thus have minimal systemic effects. Beta emitters can cause significant cutaneous burns and scarring. Due to their ability to penetrate tissue, gamma emitters can cause not only local damage but also whole-body radiation exposures and injury. Medical treatment primarily entails decontamination of the body, including wounds and burns, to prevent internalization of radioactive contaminants. Removal of contaminated clothing reduces levels of contamination significantly and is a first step in the decontamination process. Generally, patients do not constitute a significant radiation hazard to health care providers, and lifesaving treatment should not be delayed for fear of secondary contamination of the medical team. Although risk is relatively low, any damage to health care personnel will depend directly on the duration of exposure and will be inversely proportional to the square of the distance from any radioactive source. Gowns that can be easily removed offer protection.

Internal contamination occurs when radioactive material is inhaled or ingested or enters the body through open wounds or burns or via skin absorption. In principle, any externally contaminated casualty should be evaluated for internal contamination. Because of their chemical properties, some isotopes may exert toxic effects on specific target organs in addition to causing radiologic injury. The respiratory system is the main portal of entry for internal contamination, and the lung is the organ at greatest risk. Aerosol particles <5 μm in diameter can reach the alveoli, whereas larger particles will remain in the proximal airways. The tiny particles can be absorbed by the lymphatic system or the bloodstream. Bronchial lavage is often a helpful treatment in this situation. Radioactive material entering the gastrointestinal tract is absorbed according to its chemical structure and solubility. The insoluble radionuclides may affect the lower gastrointestinal tract. Intact skin is normally an effective barrier to most radionuclides. Penetration through the skin usually takes place when wounds or burns have compromised the skin barrier. Therefore, any skin erosion should be cleaned and decontaminated promptly.

Absorbed radioactive materials travel throughout the body. Liver, kidney, adipose tissue, thyroid, and bone and bone marrow tend to bind and retain radioactive material more than other tissues do. Medical treatment thus includes the prevention of absorption, the reduction of incorporation, and the enhancement of elimination (see below).

Localized exposure refers to close contact between a highly radioactive source and a part of the body, with consequent discrete damage to the skin and deeper tissues that resembles a thermal burn. Later signs include epilation, erythema, moist desquamation, ulceration, blistering, and necrosis in proportion to exposure. Alopecia, transient or permanent, is dose related and starts at cutaneous doses of >3 Gy. Overt tissue damage can take weeks or even months to develop; the healing process can also be very slow, lasting for months. Long-term cutaneous changes, including keratosis, fibrosis, and telangiectasis, may appear years after the exposure. Treatment is based on analgesia and infection prophylaxis. Nevertheless, severe burns often require grafting or even amputation. Long-term radiation effects are characterized by cell loss, cell death, and tissue atrophy.

Radiologic dispersal incidents are generally of two types, resulting from small, usually localized sources or from wide dispersals over large areas. The methods that could be utilized to formulate an attack using dispersal of radiation are incredibly diverse. Radioactive materials can take the form of solid state, aerosol, gas, or liquid. They can be put into food or water, released from vehicles, or spread by explosion. The principal route of exposure is usually direct contact between the victim’s skin and the radioactive particles, although internal contamination can occur if the material is inhaled or ingested. The radiation field is also a potential source of whole-body exposure. The psychosocial effects that accompany such an event are significant and are beyond the scope of this chapter. A list of radioactive materials, including information on their major properties and medical treatment, is given in Table 263e-1.

In a localized event, the amount and spread of the radioactive materials are usually limited and can be treated like a spill of hazardous material. Protective clothing prevents or minimizes the contamination of emergency responders.

The use of explosives coupled with a large amount of radioactive materials can result in wide dispersion of radiation, which is of far greater concern. Other potential sources of radiation are nuclear reactors, spent nuclear fuel, and transport vehicles. Less probable but still possible is the use of a large source of penetrating radiation without explosion. It is expected that most exposures would be low-level and that the principal health and psychosocial effects would be similar to those in the former scenario but on a larger scale. Whenever an explosion is involved, conventional lifesaving treatment should be given first priority. Only then should decontamination and specific treatment be given for the radiation exposure.

Silent exposure represents a scenario in which a powerful radiologic source, often called a radiologic exposure device, could be hidden in a crowded place and spread radioactive materials without being recognized or reported. Recognition of the event and the source of exposure might take a long time. A major clue in this situation is the appearance of unusual clinical manifestations in many individuals; such manifestations are often nonspecific and include symptoms of acute radiation sickness (see “Acute Radiation Syndrome,” below) such as headache, fatigue, malaise, and opportunistic infections. Gastrointestinal phenomena such as diarrhea, nausea, vomiting, and anorexia may occur. Dermatologic symptoms (e.g., burns, ulceration, and epilation) and hematopoietic manifestations (e.g., bleeding tendency, thrombocytopenia, purpura, lymphopenia, and neutropenia) are also possible and are dose-related. Careful epidemiologic studies may be necessary to identify the source of such exposure.

The most likely scenario in a nuclear terror attack is the detonation of a single low-yield device. The estimated yield of such a device is anywhere between 0.01 and 10 kilotons of 2,4,6-trinitrotoluene (TNT). The expected effects of such an explosion are a combination of several components: ground shock, air blast, thermal radiation, initial nuclear radiation, crater formation, and radioactive fallout.

A nuclear detonation, like a conventional explosion, produces a shock wave that can further damage structures and cause many casualties. In addition, the detonation can produce an extremely hot fireball that can ignite materials and cause severe burns. The detonation releases an intense pulse of ionizing radiation consisting mainly of gamma rays and neutrons. The radiation produced in the first minute is termed initial radiation, whereas the ongoing radiation due to fallout is termed residual radiation. Both types of radiation can cause acute radiation sickness, and winds can carry fallout and contaminate large areas. The LD_50/30 (i.e., the dose that causes a 50% mortality rate at 30 days) is ~4 Gy for whole-body exposure without medical support; with medical support, the LD_50/30 ranges between 8 and 10 Gy. On top of its immediate effects, a massive blast forms a crater in the soil and usually produces ground shock that compounds the physical damage and the number of casualties. Inhalation of large amounts of radioactive dust causes pneumonitis that can lead to pulmonary fibrosis. Use of a mask covering the mouth and nose can result in effective prevention. The intense flash of infrared and visible light can cause either temporary or permanent blindness. Cataracts can develop months to years later among survivors.

Acute radiation syndrome (ARS) refers to multisystem symptomatology resulting hours to weeks after radiation exposure. As discussed earlier, cell sensitivity to radiation damage increases as the cell replication rate increases and as cell differentiation decreases. Bone marrow and mucosal surfaces of the gastrointestinal tract, which have vast mitotic activity, are significantly more sensitive to radiation than are slowly dividing tissues such as bones and muscles. After exposure of all or most of the human body to ionizing radiation, ARS can develop. The clinical manifestations of ARS reflect the dose and type of radiation as well as the parts of the body exposed.

ARS manifests as three major groups of signs and symptoms: hematopoietic, gastrointestinal, and neurovascular. In addition, ARS exists in four stages: prodrome, latent phase, clinical illness, and recovery or death. The higher the radiation doses, the shorter and more severe each stage. The prodrome appears within minutes to 4 days after exposure, lasts from a few hours to a few days, and can include nausea, vomiting, anorexia, and diarrhea. At the end of the prodrome, ARS progresses to the latent phase. Minimal or no symptoms are present during the latent phase, which commonly lasts up to 2.5 weeks but can last up to 6 weeks. The duration depends on the radiation dose, the prior health of the patient, and coexisting illness or injury. After the latent phase, the exposed person manifests illness that may end in recovery or lead to death.

With exposure to low doses of <1 Gy, ARS is generally mild. At this dose, symptoms can be minimal or nonexistent, even if the entire body is exposed to penetrating radiation. The main feature of the clinical picture is transient depression of bone marrow (lymphopenia) that lasts up to 2–3 weeks and then improves.

ARS is significantly more acute and severe with exposure to very high radiation doses (>30 Gy). At these doses, the prodrome appears in minutes and is followed by 5–6 hours of latency before cardiovascular collapse occurs secondary to irreversible damage to the microcirculation.

Exposure to intermediate radiation doses may result in variable ARS courses. The type and dose of radiation and the part of the body exposed determine not only the timing of the different stages of ARS but also the dominant clinical picture. At low radiation doses of 0.7–4 Gy, hematopoietic depression due to bone marrow suppression is the main constituent of illness. The patient may develop infection and bleeding secondary to low leukocyte and platelet counts, respectively. The bone marrow eventually recovers in almost all patients if they are supported with transfusions and fluids; antibiotics are often needed in addition. Patients with isolated hematopoietic manifestations of ARS can almost always survive with proper supportive care. After exposure to 6–8 Gy, a significantly more complicated clinical picture may ensue. At these doses, the bone marrow does not always recover and death may occur as a result. A gastrointestinal syndrome may accompany the hematopoietic manifestations and further worsen the patient’s condition. Gastrointestinal injury due to compromise of the absorptive layer of the gut alters absorption of fluids, electrolytes, and nutrients. Such injury can lead to vomiting, diarrhea, gastrointestinal bleeding, sepsis, and electrolyte and fluid imbalance. Generally, these symptoms are also accompanied by a severe hematopoietic syndrome, with only a slim chance of bone marrow recovery. These factors in constellation often lead to death. Whole-body exposure to >9–10 Gy is almost always fatal. Crucial elements of the bone marrow simply do not recover. In addition to the gastrointestinal syndrome associated with very high-level exposures, patients may develop a neurovascular syndrome that includes vascular collapse, seizures, and confusion; death occurs within a few days. The neurovascular syndrome dominates after whole-body exposure to >20 Gy. In this variant, the prodrome and latent phase both last only a few hours.

TREATMENT

Victims of radiation bioterrorism can suffer from conventional thermal or blast injuries, exposure to radiation, and contamination by radioactive materials. Many will have combinations of the above, which can cause higher morbidity and mortality rates than each exposure would alone. The number of casualties will be a major factor in determining the response of the medical system to an act of radiation bioterrorism. If only a few persons are affected, no significant changes and adaptations of the system are needed to treat the victims. If a terror attack results in dozens of casualties or more, however, an organized disaster plan at the local and state levels must be invoked to deal with the crisis properly. Useful U.S. planning documents that include many universal planning concepts can be found at http://www.remm.nlm.gov/remm_Preplanning.htm. Ideally, medical personnel will have had a prior assignment and training and be prepared to function in a scenario with which they are familiar. Stockpiles of specific equipment and medications should be obtained ahead of time and stored safely (see the Centers for Disease Control and Prevention Web site at http://www.bt.cdc.gov/stockpile/). One of the goals of terrorist attackers is to overwhelm medical facilities and minimize the salvage of casualties. Initial management consists of primary triage and transportation of the wounded to medical facilities for treatment. The rationale behind triage is to sort patients into classes according to the severity of injury for the purpose of expediting clinical care and maximizing the use of the available clinical services and facilities. Triage requires determination of the level of emergency care needed. The higher the number and broader the range of casualties, the more complex and difficult triage becomes. The mildly wounded and victims of contamination only can be sent to evacuation, registration (with disaster response teams), and decontamination/treatment centers. Figure 263e-2 illustrates an evacuation scheme after a radiologic event causing multiple casualties. The goal of such an algorithm is to treat all possible victims of exposure and minor injury outside of the hospital setting. This approach prevents hospitals from being directly overwhelmed and enhances treatment for persons who are severely wounded. Emergency treatment should be administered initially for conventional injuries such as wounds, trauma, and thermal or chemical burns. Individuals with such injuries should be stabilized, if possible, and immediately transported to a medical facility. Removing clothing and wrapping the victim in clean blankets or nylon sheets reduce both the exposure of the patient and the contamination risk to the staff. Less severely injured victims should undergo preliminary decontamination before or during evacuation to a hospital.

One must remember that radionuclide contamination of the skin commonly is not an acute life-threatening situation for the patient or for the personnel who care for the patient. Only powerful gamma emitters are likely to cause real damage from contamination. It is important to emphasize that exposure to a radiation field alone does not necessarily create any contamination. The exposed person, if not contaminated, is not radioactive and does not directly emit any radiation.

To protect the staff, protective gear (gowns, gloves, masks, and caps) should be used. Protective masks with filters and chemically protective overgarments provide excellent protection from contamination. Waterproof shoe covers are also important. Remaining in the contaminated area and dealing with lifesaving procedures should take place according to the “ALARA” principle: as low as reasonably achievable. It is better to send many people to do the job for short exposure times than to send a few people for longer periods.

Decontamination of victims should take place in the field before their arrival at medical facilities, but radiologic decontamination should never interfere with medical care. Removal of outer clothing and shoes usually reduces a patient’s contamination by 80–90%. Contaminated clothes should be carefully removed by rolling them over themselves, placed in marked plastic bags, and removed to a predefined area for contaminated clothes and equipment. A radiation detector should then be used to check for the presence of any residual radiologic contamination on the patient’s body. To prevent internalization of the radioactive materials, one should cover open wounds before decontamination. Showering or washing of the entire skin and hair is very important and should be done as soon as possible. The skin should then be dried and reassessed for residual contamination until no radiation is found. Contamination-removing chemical agents are more than sufficient to remove radiologic contamination.

Wound decontamination should be as conservative as possible. The main goal is to prevent both extensive local damage and internal contamination through lacerated skin. The bandages should be removed and the wounds flushed. The wound should then be dried and assessed for radiation. This procedure can be repeated again and again until contamination is undetectable. Excision of contaminated wounds should be attempted only when surgically necessary. Radioactive shrapnel that can penetrate through the skin should be removed.

In the hospital, staff can wear normal hospital barrier clothing, including two pairs of gloves, a gown, shoe covers, a head cover, and a face mask. Eye protection is recommended. Decontamination of medical personnel is obligatory after emergency treatment and decontamination of the patient. After use, all protective clothing should be placed in a designated container for contaminated clothing.

Radiation intensity decays rapidly with the square of the distance from the source; thus increasing the distance from the source and decreasing the time spent near it are basic principles of radiation safety. Shielding with lead can be used as protection from small radioactive gamma sources. Geiger counters can detect gamma and beta radiation. Pocket chambers and dosimeters, film badges, and thermoluminescent dosimeters can measure accumulated exposure to gamma radiation. All these detectors are in common use in medical facilities and should be employed to help define the level of contamination. Alpha radiation is harder to detect due to its poor penetration. An alpha scintillation counter, which is capable of detecting alpha radiation, is not commonly used in medical facilities.

Figure 263e-3 shows a model for hospital arrangement for triage. Persons contaminated either externally or internally should be identified, externally decontaminated, and, if need be, treated immediately and specifically for internal contamination as detailed below. In all other cases, the need for treatment of radiation injuries does not constitute a medical emergency. Early actions—e.g., blood sampling both to assess the severity of the exposure and to perform blood typing and cross-matching for possible transfusion—need to be taken promptly if ARS is evident or if whole-body exposure is suspected.

In the hospital entrance, a distinct decontamination area should be set up promptly. Separation between clean and contaminated areas is essential. Medical personnel in contaminated areas should wear protective gear, as noted above, and should be rotated in their assignments every 1–2 h to ensure minimal exposure to radiation. If patients are critically wounded and require either surgery or resuscitation, they need to be transported directly to “contaminated” operating rooms or resuscitation sites for lifesaving procedures. Once the condition of such patients is stable, they should be decontaminated. It is important to obtain details concerning the exposure, to look for prodromal signs of radiation sickness, and to conduct a physical examination. One of the simplest ways to estimate exposure clinically is to measure the time of prodromal appearance. The earlier the prodromal signs and symptoms appear, the higher is the dose of radiation exposure. A few laboratory tests need to be done routinely, such as complete blood count and urinalysis. If internal contamination is suspected, specific treatment should be given as outlined below.

TREATMENT

One of the major difficulties in treating victims exposed to radiation is determination of the amount of exposure. Immediately after a terrorist event, when victims are being triaged, information regarding source, dose, and exposure time is unlikely to be available. Clinical assessment of the patient is the best approach and includes history, physical examination, and observation for onset of the ARS prodrome. An early prodrome indicates high-level exposure to radiation. Victims who arrive at the hospital reporting severe weakness, nausea, vomiting, diarrhea, or seizures probably will not survive despite supportive measures. A very limited number of tests can be performed to estimate radiation exposure and contamination. The Biodosimetry Assessment Tool (BAT) facilitates treatment decisions during radiation exposure incidents. Developed by the U.S. Armed Forces Radiobiology Research Institute (AFRRI), the BAT provides a method of estimating radiation exposure on the basis of a single lymphocyte count, the lymphocyte depletion rate, and the time from exposure to onset of emesis. The BAT algorithms are based on large datasets from human radiation exposure and are available at http://www.usuhs.mil/afrri/outreach/request.htm. The patient should be observed for clinical symptoms, and the severity and time of onset of nausea, vomiting, headache, anorexia, fever, hypotension, tachycardia, weakness, cognitive changes, skin desquamation, diarrhea, and bloody stools should be recorded. The AFRRI Biodosimetry Worksheet (http://www.usuhs.mil/afrri/outreach/pdf/afrriform331.pdf) is a useful resource for detailed recording. Baseline tests should include a complete blood count with differential and platelet count, renal evaluation, and determination of electrolytes, serum amylase, and serum C-reactive protein. Urine and stool samples should be obtained if internal contamination is suspected. Nasal swabs taken from each nostril within the first 1–2 h after the exposure may be useful for determination of radionuclide inhalation. After exhalation, each swab is labeled, sealed in a plastic bag, and sent for analysis to appropriate laboratories. Patients exposed to 0.7–4 Gy develop pancytopenia from as early as 10 days to as late as 8 weeks after exposure. Lymphocytes show the most rapid decline, whereas counts of other leukocytes and platelets decline less rapidly. Erythrocytes are the least vulnerable blood elements.

Absolute lymphocyte counts should be repeated every 4–6 h for 5–6 days; they are the most valuable early indicator because they constitute a sensitive marker for radiation damage and correlate with both the exposure and the prognosis. A 50% drop in absolute lymphocyte count within the first 24 h indicates a significant injury. HLA typing is necessary whenever irreversible bone marrow damage is suspected. Lymphocyte chromosomal analysis can detect exposure to as little as 0.03–0.06 Gy, and 15 mL of blood for this purpose should be drawn as early as possible in a heparinized collection tube and kept cool. Radiation-induced chromosomal aberrations visible in peripheral-blood lymphocytes include dicentric chromosomes and ring forms that last for a few weeks. Calibration of a dose-response curve makes it possible to assess the radiation dose on the basis of the presence of these aberrations. Dicentric quantification requires multiple days to perform and is available only in select centers.

Another method for estimating exposure is the in vitro cytokinesis–block micronucleus assay. Micronuclei can be the result of small acentric chromosome fragments that arise during exposure to radiation. The technique to score the micronuclei in peripheral-blood lymphocytes has been standardized in the last few years. It can be a useful tool in small-scale exposures but is not feasible in a mass casualty setting.

It is desirable to continue follow-up over the long termin some circumstances. In general, only persons who are exposed to <8–10 Gy of whole-body irradiation have a chance to survive in the long term, and they are at risk of developing cataracts, sterility, and cancers as well as lung, kidney, and bone marrow problems. In light of their age, their gender, and the amount and type of exposure, they should be followed for many years. A major public health issue is the risk of secondary malignancy in individuals and populations that have been exposed to low doses of radiation. Leukemia and breast, brain, thyroid, and lung cancer develop most commonly, but the exposed population is at increased risk for many other cancers as well. Appropriate follow-up protocols should be based on the type of exposure and the exposed population. In cases of internal contamination, long-term follow-up should be focused on the organ at risk. Substantial psychosocial support will likely be needed for a community in the years after an attack including radiologic agents.