Firefighters rescued the driver of the U.S. Postal Service semitractor-trailer when they responded to the intersection of 37th and Flower streets at about 8:31 p.m. after the driver lost control while on the southbound 110.
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The California Highway Patrol said it appears the truck lost control because a red Audi was traveling at a high speed and hit the trailer of the big rig. Two people inside the red vehicle fled the scene on foot, according to CHP.
Witnesses said the Audi appeared to be going at about 100 mph.
The driver of the truck, believed to be approximately 50 years old, was transported in critical condition to a nearby trauma center.
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Hundreds of packages went onto the street and the crash separated the vehicle's cab from the trailer.
Other postal trucks were brought in to collect the mail scattered.
The whereabouts of the two people inside the red vehicle are not known.
Police are looking for the two men who investigators say caused the crash.