INTRODUCTION — Subcutaneous immunotherapy (SCIT) is administered differently around the world and even within the United States. Over the past few decades, professional allergy societies in the United States have made attempts to reduce variations in practice and identify best approaches. Practice parameters for SCIT have been published, and the approach described in this topic review is consistent with the American guidelines .
Terminology — An allergen immunotherapy extract is a solution of one or more allergens that is used for immunotherapy. This topic review will use the term "allergen immunotherapy extract" or "allergen extract," although other terms in use include "allergy serum," "allergen vaccine," "allergen solution," and "allergen product" .
The preparation of allergen extracts for use in SCIT, including effective doses, types of extracts, mixing of different allergens, training of compounding personnel, storage and stability, and recording of prescriptions for allergen immunotherapy will be discussed in this topic review. Administration techniques, schedules, and choice of allergens, as well as an overview of the manufacture of allergen extracts are reviewed separately. (See "Subcutaneous aeroallergen immunotherapy: Accelerated schedules (cluster and rush)" and "Allergen extracts: Composition, manufacture, and labeling".)
TYPES OF ALLERGEN EXTRACTS — Several types of allergen stock solutions are available from commercial sources in the United States. The allergen may be in an aqueous solution, a solution containing 50 percent glycerin, in an alum-precipitated form, or lyophilized. The manufacture of allergen extracts is reviewed in detail separately. (See "Allergen extracts: Composition, manufacture, and labeling" and 'Dilutions and diluents' below.)
A specific allergen may only be available in a limited number of forms. As examples:
●Most pollens are available in either aqueous solutions or 50 percent glycerin solutions. Glycerin is a stabilizing and bacteriostatic agent, but it can cause pain at the injection site in a dose-dependent manner. The standardized extracts of house dust mites, cat dander, and grasses are only available in 50 percent glycerin. Some pollens are also available in an alum-precipitated formulation.
●Fungal (mold), fire ant, and cockroach extracts are often available in aqueous or 50 percent glycerin solutions, but only the 50 percent glycerin should be used because solutions containing less glycerin are prone to autodigestion due to the relative abundance of proteolytic enzymes that naturally occur in these substances .
●There is only one line of alum-precipitated extracts approved in the United States and only pollen extracts are available in this line. Alum-precipitated extracts are less prone to cause systemic reactions due to retarded systemic absorption from the injection site. The disadvantage of the available alum-precipitated extracts is that they contain less allergen than concentrated aqueous or glycerinated pollen extracts, thus limiting the number of extracts that can be combined in an allergen immunotherapy extract and still deliver an optimal dose.
●Dog extracts exist in aqueous and glycerinated forms, although only the acetone-precipitated (AP dog) (glycerinated) product has been shown to be sufficiently potent to deliver an adequate immunotherapy dose [3,4].
●The only lyophilized products are the Hymenoptera venoms.
Aside from the exceptions mentioned above (AP dog and alum-precipitated pollen extracts), there is no compelling scientific reason to favor one company over another as a source of allergen extracts.
Glycerinated, aqueous, and alum-precipitated extracts can be mixed, provided there are no compatibility issues. (See 'Compatibility of allergen extracts' below.)
Standardized — Standardized extracts are preferred over nonstandardized extracts, although standardized extracts are not available for all allergens. Standardization refers to the way in which an allergen extract is produced and takes into account multiple factors, such as selection and collection of raw materials, extract preparation, storage, validation of assays, and reagents for batch-to-batch control. Standardization is intended to minimize variations in the composition and quality of allergen in the final product. The processes involved in standardization are reviewed in more detail separately. (See "Allergen extracts: Composition, manufacture, and labeling", section on 'Standardization of allergen extracts'.)
Standardized extracts offer the advantage over nonstandardized extracts of more consistent potency, although a certain degree of variability is allowed. However, although they are consistent in content of major allergen or overall allergenicity (depending on which was the basis for standardization), there is no attempt to ensure consistency in the relative contents of minor allergens. Despite these limitations, standardized extracts are preferred over nonstandardized extracts.
At the time of this review, the available standardized extracts are:
●Cat hair or pelt (expressed as bioequivalent allergy units [BAU]/mL), which is standardized by the content of the major allergen, Fel d 1.
●Dermatophagoides pteronyssinus and D. farinae (expressed as allergy units [AU]/mL), which were initially standardized by quantitative skin testing in highly allergic subjects and subsequently standardized to the reference extract by in vitro methods.
●Short ragweed (expressed as weight of extracted material divided by amount of extracting fluid [w/v], but with the content of the major allergen, Amb a 1, listed on the label expressed as FDA units). A concentration of 350 FDA units/mL has been determined to be equivalent to 100,000 AU/mL .
●Bermuda grass and northern pasture grasses (Timothy, Kentucky Blue, Perennial Rye, Orchard, Meadow Fescue, Redtop, and Sweet Vernal) expressed as BAU/mL, which were initially standardized by quantitative skin testing in highly allergic subjects and subsequently standardized to the reference extract by in vitro methods.
●Hymenoptera venoms (yellow jacket, honey bee, wasp, yellow hornet, and white-faced hornet) are expressed as micrograms of venom protein/mL and standardized on the basis of a venom protein content of 100 mcg/mL for individual species and 300 mcg/mL for the mixed vespids.
Nonstandardized — The remaining pollens (ie, all tree pollens, weed pollens except short ragweed), animal dander (except cat), insect (eg, cockroach and imported fire ant), and fungal extracts are not standardized. The potency of nonstandardized extracts is expressed as w/v or in terms of protein nitrogen units (PNU). These expressions of potency have been shown to have little or no relationship to allergenic potency. Hence, nonstandardized extracts labeled as the same strength cannot be assumed to be of similar potency, either between companies or on a lot-to-lot basis within a company. This lot-to-lot variation in potency is important when preparing a replacement allergen immunotherapy extract. A more potent extract can lead to a systemic reaction unless the dose is appropriately reduced. When changing from an older to a newer vial of allergen immunotherapy extract, it is customary to reduce the volume of the patient's dose by one-third to one-half (eg, from 0.5 mL of maintenance 0.35 to 0.25 mL), even though the same extracts from the same manufacturer are used to compound the new extract. The dose can then be built back up to the dose the patient was previously receiving. This reduction in dose is done because the fresh vials may be more potent due to gradual degradation of proteins in the old vials or variations in allergen content among different lots of extract. The various units used in labeling allergen extracts are reviewed separately. (See "Allergen extracts: Composition, manufacture, and labeling", section on 'Units of measure'.)
Since nonstandardized and standardized pollen extracts are of similar potency, non-standardized pollen extracts can be presumed to be clinically effective at similar doses to those used for standardized pollen extracts, even though randomized, controlled studies have not been performed.
DOSING — The effectiveness of SCIT is dose-dependent. The optimal dose or dose range is specific to each type of allergen and varies significantly among allergens. Optimal doses have been determined for many of the major inhalant allergens .
Standardized extracts — Doses of individual standardized allergens that produced clinically effective results in double-blind, placebo-controlled trials are known for the standardized allergens (table 1) . The following points should be noted:
●In some cases, lower doses that are ineffective are known from trial data.
●For many of these extracts, no studies have been conducted with the standardized extracts available in the United States. Standardized extracts of short ragweed in the United States do list amounts of Amb a 1 in FDA units (which are equivalent to micrograms) on the label, but the others do not (table 1). The values in the tables (table 1 and table 2) are based in most cases on analysis of dozens of extracts from all manufacturers in the United States . If information about the amount of major allergen in micrograms in a particular lot of extract is not available, then this information about average content can be used instead.
●The potencies of the standardized pollen extracts (which are manufactured from relatively pure samples of pollen), as reflected in their allergy units (AU) or bioequivalent allergy units (BAU) values, are approximately 10 times greater in major allergen content compared with standardized extracts of perennial allergens, such as house dust mites and cat.
Nonstandardized allergens — Data on effective doses and examples of major allergens are given in the table for a number of nonstandardized extracts (table 2) . It should be noted that the nonstandardized pollens are generally in the same range of potency as the standardized pollens.
Because of the relatively low content of major allergen in nonstandardized extracts of cockroach, fungi, and aqueous preparations of dog dander, it is uncertain whether clinically effective immunotherapy doses can be attained with these extracts. However, there are fully controlled trials showing effective immunotherapy with Alternaria alternata  and Cladosporium herbarum , as well as unblinded and/or uncontrolled studies reporting favorable patient outcomes with cockroach  and horse dander  immunotherapy using available extracts. In contrast, in comparison with conventional extract, only acetone-precipitated (AP) dog extract is sufficiently potent to achieve effective dosing [3,4].
CREATING A MAINTENANCE ALLERGEN EXTRACT — Available studies about optimal dosing form the basis of recommendations in immunotherapy practice parameters (table 3) . The doses recommended in the practice parameters are based upon data in the tables (table 1 and table 2), literature review, and expert panel clinical experience.
An allergen immunotherapy extract should be prepared so that the maintenance concentration delivers a dose of each allergen that has been demonstrated to be clinically effective (called the maintenance goal). This is typically delivered in a volume of 0.2 to 0.7 mL, although the lower end of this volume range is preferred if the maintenance solution contains significant glycerin. Specifically, extract manufacturers advise administering no more than 0.2 mL of a 50 percent glycerin solution to avoid pain at the injection site .
Allergen immunotherapy dosing is not adjusted for patient size or age. Children have customarily been given the same dose as adults. Some patients may not tolerate this dose due to repeated large local or systemic reactions. In this situation, the patient's highest tolerated dose becomes his/her maintenance dose.
To prepare a 10 mL vial of Timothy grass maintenance extract, one would proceed as follows: If a 0.5 mL maintenance volume is desired, then a 10 mL vial should contain 20 doses. Based on the recommended effective dose for Timothy grass, which is 3000 BAU the vial should contain 20 x 3000 or 60,000 BAU. Since the Timothy extract comes as 100,000 BAU/mL, 0.6 mL of the full-strength Timothy extract should be placed in the 10 mL vial. The remaining 9.4 mL would be diluent if the patient were only receiving Timothy, or the diluent could be partially replaced by other compatible allergen extracts in appropriate amounts, if the patient required treatment with multiple allergens. This would be the full-strength maintenance extract. Serial dilutions to be used during the build-up phase would then be prepared from this maintenance concentration. (See 'Multiple allergen immunotherapy extracts' below.)
For clinicians who do not wish to prepare patient allergen extracts, "treatment sets" can be prepared and purchased through extract manufacturers. The clinician must write a prescription for the specific allergens and amounts of each that are to be included for that patient's therapy.
Dosing of Hymenoptera venom immunotherapy and fire ant immunotherapy is somewhat different from that of the aeroallergens and is reviewed elsewhere. (See "Hymenoptera venom immunotherapy: Technical issues, protocols, adverse effects, and monitoring", section on 'Dosing' and "Stings of imported fire ants: Clinical manifestations, diagnosis, and treatment", section on 'Venom immunotherapy'.)
Recommendations have been made for creating maintenance allergen extracts from nonstandardized extracts, although these are based upon limited data:
●For nonstandardized pollens, a target dose of 0.5 mL of a 1:100 or 1:200 weight/volume (w/v) solution is reasonable, which is achieved by adding 1 mL of the full-strength (1:10 or 1:20 w/v) extract to a 10 mL vial .
●For nonstandardized fungal (mold) and cockroach extracts, only glycerinated extracts can be recommended and amounts added should be greater than for pollens . It is uncertain if sufficient amounts of these weak extracts can be administered to be clinically effective. Many clinicians will add the maximum amount possible. These extracts should not be combined with pollen, house dust mite, or dog or cat dander extracts, nor should fungal and cockroach allergen extracts be combined in the same vial .
●Only acetone-precipitated dog extract (AP dog) can be recommended for immunotherapy. AP dog comes as a 1:100 w/v stock solution which contains, on average, 140 mcg of Can f 1/mL . With an effective dose of 15 mcg of Can f 1, this would mean adding 2.1 mL of the stock solution to the 10 mL vial.
Multiple allergen immunotherapy extracts — Most patients placed on immunotherapy are sensitized to multiple allergens [13-15]. In the United States, the use of immunotherapy solutions containing multiple allergens is the rule, while in many other countries, patients are treated with the single allergen to which the patient shows greatest clinical sensitivity. Both methods have been shown to be effective in randomized, controlled studies [16-19]. However, direct, head-to-head studies comparing the two approaches are lacking. In a large, randomized trial of patients receiving grass SCIT, both monosensitized and polysensitized patients benefited to a similar degree from monotherapy with grass pollen extract . (See "Subcutaneous immunotherapy (SCIT) for allergic rhinoconjunctivitis and asthma: Indications and efficacy".)
The table shows the effective dose ranges, examples of commercially available extracts (in the United States), recommended doses per maintenance injection, amount to add to 10 mL maintenance vial, and mixing limitations (table 4).
To prepare a 10 mL vial containing multiple compatible allergens, calculations are performed for each allergen and then diluent is used to fill the vial to 10 mL. As an example, a vial containing Timothy grass pollen, birch tree pollen, and short ragweed pollen extracts could be mixed as follows:
●Timothy – 0.6 mL of the standardized Timothy extract would be placed in the 10 mL vial. (See 'Creating a maintenance allergen extract' above.)
●Birch – This nonstandardized extract is available in a 1:10 w/v aqueous or a 1:20 w/v glycerinated solution and it is recommended that 1 mL of nonstandardized pollen extracts be added to a 10 mL maintenance vial .
●Short ragweed – The recommended maintenance dose is 2500 AU (allergy units), so 2500 x 20 or 50,000 AU should be placed in the 10 mL vial. This standardized extract comes as 100,000 AU/mL, so 0.5 mL is placed in the vial.
●Diluent – The extracts total 2.1 mL, so 7.9 mL of diluent is added to fill the 10 mL vial.
Dilutions and diluents — Once the maintenance strength of an allergen immunotherapy extract is prepared, serial 10-fold dilutions are made to be used during the build-up phase of immunotherapy. These are labeled in units of volume/volume (v/v) (note that this is different from w/v used for individual allergen extracts): 1:10 v/v, 1:100 v/v, 1:1000 v/v, and 1:10,000 v/v. Guidelines have recommended a standardized color coding to reduce the likelihood of dosing errors. In the United States, there is a convention for the color of the cap used for different strengths :
●The maintenance vial is labeled 1:1 v/v and is given a red cap
●1:10 v/v has a yellow cap
●1:100 v/v has a blue cap
●1:1000 v/v has a green cap
●1:10,000 v/v has a silver cap
In some clinics, the lowest dilution used to begin the build-up is 1:1000 v/v, and in others, 1:10,000 v/v is preferred. Extracts may be diluted even further for exquisitely-sensitive patients.
Diluent options — Dilutions can be made with one of several diluents:
●Saline with 0.4 percent phenol
●Saline with 0.4 percent phenol and 0.03 percent human serum albumin (HSA)
Phenol — Phenol is a bacteriostatic agent that is added to aqueous extracts, normal saline, and HSA solutions. Phenol is required in all immunotherapy extracts, with the exception of 50 percent glycerin. Phenol has the disadvantage of having been shown to cause loss of potency over time with some extracts .
Human serum albumin — Human serum albumin (HSA) is added to dilute extracts to retard loss of potency , in part by reducing adsorption of the allergenic proteins to the surface of the vial. It may also protect against the negative effects of phenol on some extracts .
Glycerin — At a concentration of 50 percent, glycerin acts as a bacteriostatic agent and also inhibits much of the proteolytic activity found in fungal and cockroach extracts, but this concentration of glycerin causes injection site pain (although not local reactions ) in most patients. A prospective study found that significant pain due to glycerin was rare if the total injected glycerin dose was <0.05 mL (total injected glycerin dose = injection volume x glycerin concentration) . At lower concentrations than 50 percent, glycerin is less effective as a bacteriostatic agent, and phenol should be added. At 10 percent, glycerin may provide some protection against loss of extract potency but is inferior to HSA, at least for pollen and house dust mite extracts .
OTHER CONSIDERATIONS — Other important issues to consider when prescribing or producing maintenance extracts include cross-allergenicity among allergens, compatibility of different allergens, and individual vials versus shared extracts.
Cross-allergenicity among allergens — There are clusters of related allergens that are sufficiently similar that just one of the group is required to generate immunologic changes to the entire group. These clinically relevant cross-reacting allergens are listed in the table (table 5). In this situation, one of two approaches is appropriate:
●The most locally important allergen may be used alone as a representative of the group
●A mixture of the cross-reacting allergens can be substituted for a single allergen extract
The local prevalence of allergenic plants can be determined from field observation or contacting local extension services or allergen extract manufacturers. In addition, (in the United States) the National Allergy Bureau (NAB)  can provide local pollen counts if there is a counting station in the vicinity.
Compatibility of allergen extracts — Fungal (mold) and cockroach extracts contain proteases that can degrade other types of allergens. Therefore, they should not be mixed with each other or with other allergens in the same treatment vials. It is unclear if degraded allergens are less effective for immunotherapy, but there is also a safety issue. Degradation can reduce the ability of allergens to react with allergen-specific immunoglobulin E (IgE), so there is a potential risk that a patient who was receiving degraded allergens and is then exposed to a new vial of freshly mixed allergens could suffer a systemic allergic reaction.
The following applies to mixing of extracts within treatment vials:
●Fungal and cockroach extracts should not be mixed with pollen, house dust mite, or animal danders [26-28] or with each other . Thus, fungal and cockroach extracts should not contain any other types of allergens.
●House dust mite, animal danders, and pollens can be mixed with each other.
Individual versus shared allergen immunotherapy extracts — The immunotherapy practice parameters recommend individually prepared and labeled vials in preference to shared vials used for multiple patients . Potential advantages of patient-specific vials include:
●Lower risk of administering the wrong solution because the vial can be labeled with specific patient identifiers.
●The need for less frequent mixing and turnover of vials, since only one patient is using a given set of vials.
●The extracts can be more precisely tailored to an individual patient's sensitivity. Shared vials commonly use mixes of allergens (eg, mixed trees, mixed weeds) that may have components to which the patient is not sensitized, thus diluting the amount of allergen relevant to that patient and raising the possibility of new sensitization to component allergens to which the patient is not sensitized .
However, the clinical efficacy and safety of shared versus individual vials has not been formally studied.
Mixing extracts in a syringe before administration — The practice of mixing allergen extracts in a syringe just before administration to a patient is not recommended, because it increases the risk of cross-contamination of the vials from which the extracts are withdrawn .
STORAGE — Once an allergen immunotherapy extract has been formulated, it should be stored at all times when not in use at 4°C (39°F). Storage should be in a dedicated refrigerator and not one used for food or specimens.
There are few studies that have evaluated the maintenance of potency of dilutions over time, although the results of one study are shown in the table (table 6) . The results suggest six-month expiration dates for the dilutions that were studied and even shorter periods for greater dilutions. Extracts in 50 percent glycerin retain potency much longer than aqueous solutions, and this is reflected in their expiration dates. The expiration date of the maintenance concentration of an allergen immunotherapy extract is that of the earliest expiration date for any of the component allergen extracts. Dilutions of the allergen immunotherapy extract degrade more readily, and the greater the dilution, the more rapid the loss of potency. This loss is reduced by the use of 0.03 percent human serum albumin (HSA) or at least 10 percent glycerin in the diluent with HSA being superior to 10 percent glycerin at least for pollen and house dust mite extracts . (See 'Diluent options' above.)
The recommendations for expiration of dilutions of Hymenoptera venom (from time of reconstitution) are: 100 mcg/mL: 12 months, 1 to 10 mcg/mL: one month, 0.1 mcg/mL: two weeks, and <0.1 mcg/mL: prepare fresh daily.
Transport of extracts — Allergen extracts that have been made for a specific patient can be transported by the patient with relative ease. Extracts can be kept at ambient temperature for brief periods of one to two days, and vials can be mailed without refrigeration as long as they are not exposed to extreme temperatures or conditions .
QUALITY CONTROL AND STERILITY
Clinician responsibility — In the United States, a clinician with training and expertise in allergen immunotherapy is responsible for ensuring that compounding personnel are instructed and trained in preparation of allergen immunotherapy extracts using aseptic technique and that they meet the requirements of current guidelines. Evidence of such compliance should be documented and maintained in personnel files. The clinician is responsible for providing general oversight and supervision of compounding personnel .
Concerns about training compounding personnel are less applicable to European countries, as most allergen immunotherapy extracts are prepared for clinical use by extract manufacturers [20,30].
Qualifications of extract preparation personnel — To ensure proficiency, compounding personnel must:
●Be trained in preparation of allergenic products
●Pass a written test to demonstrate understanding of aseptic technique and extract preparation
●Be able to identify, measure, and mix ingredients correctly
●Be able to demonstrate understanding of antiseptic hand cleaning and disinfection of mixing surfaces
●Pass an annual media fill test, which is a test to demonstrate proficiency in sterile technique
The US Pharmacopeial (USP) Convention has published guidelines: Chapter 797, Pharmaceutical Compounding – Sterile Preparations, the latest version of which was published June 1, 2019. The following summary of the standards for allergen extract compounding in these was prepared by the American College of Allergy, Asthma, and Immunology (ACAAI) Advocacy Council (table 7) .
The American Academy of Allergy, Asthma, and Immunology (AAAAI) also provides USP Chapter 797, the Allergen Immunotherapy Extract Preparation Manual, a case-based immunotherapy prescription mixing workshop video, immunotherapy forms, and a list of media-fill-test vendors .
Several tests to assess sterile technique (ie, media fill tests) are available. In one, concentrated media is transferred in 10 0.5 mL increments with a sterile syringe to a sterile 10 mL vial. The vial is incubated at 20 to 35°C (68 to 95°F) for 14 days. Failure is indicated by visible turbidity in the medium . A list of sources for the media fill test is available through the AAAAI [32,33].
DOCUMENTATION — Clear and accurate recording of the initial prescription for an allergen immunotherapy extract is essential to ensure that it is mixed in an identical fashion each time it is filled. In addition, these forms allow transmission of information to any clinician who may undertake the allergy care of the patient. It is recommended that the following information be contained in the form:
●Patient information including name, patient number, birth date, telephone number, and picture (if available), to reduce the risk of an extract being given to the wrong patient.
●Preparation information including name of person preparing and date of preparation.
●Allergen immunotherapy extract content, including (for each allergen) common name or genus and species, extract manufacturer, concentration of manufacturer's extract, volume of manufacturer's extract added, the type of diluent (if any), volume of diluent added, lot number, and expiration date of each individual component.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Allergen immunotherapy for the treatment of respiratory allergy".)
SUMMARY AND RECOMMENDATIONS
●Types of allergen preparations – An allergen immunotherapy extract is a solution of one or more allergens that is used for subcutaneous immunotherapy (SCIT). In the United States, most allergens are commercially available as aqueous or glycerinated solutions. Exceptions include a line of alum-precipitated pollens, acetone-precipitated dog (AP dog), and lyophilized Hymenoptera venoms. (See 'Types of allergen extracts' above.)
●Standardized extracts – Standardized extracts are more consistent in their potency and are thus preferred when available over nonstandardized extracts. In the United States, only cat pelt and hair, two house dust mites, short ragweed, eight grasses, and Hymenoptera venoms are available in standardized forms. (See 'Standardized extracts' above.)
●Dosing – The effectiveness of SCIT is dose-dependent. The optimal dose or dose range is specific to each type of allergen and varies significantly among allergens. Optimal doses have been determined for many of the major inhalant allergens (table 1 and table 2). Immunotherapy practice parameters provide recommended doses for maintenance immunotherapy with various standardized and nonstandardized allergens (table 3). Doses are not adjusted for the age or size of the patient. (See 'Dosing' above and 'Creating a maintenance allergen extract' above.)
●Single versus multiple allergens – In the United States, it is common to administer SCIT with a mixture of several allergens, although this is not the practice in much of the rest of the world, and the two approaches have not been compared directly. (See 'Multiple allergen immunotherapy extracts' above.)
●Mixing allergens – When mixing an allergen extract for use in SCIT, it is important to understand cross-allergenicity among similar allergens and compatibility among different allergens. (See 'Other considerations' above.)
●Storage and quality control – Allergen extracts should be stored at 4°C (39°F). The length of time that an extract can be stored is mainly determined by its concentration, since more dilute extracts are the least stable. Personnel involved in mixing allergen extracts should undergo training and fulfill various requirements to document satisfactory techniques. (See 'Storage' above and 'Quality control and sterility' above.)
●Documentation – Accurate recording of the initial prescription for a patient’s allergen immunotherapy extract(s) is essential to ensure that solutions are prepared in an identical fashion each time they are needed. In addition, precise documentation is critical if oversight of immunotherapy is transferred from one clinician to another. Forms are available to ensure the proper information is included (form 1). (See 'Documentation' above.)
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