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He assigned Pedro Arias Dávila (Pedrarias Davila) as Royal Governor.
Pedrarias arrived in June 1514 with a 22 vessel, 1,500 men armada.
Governor Pedrarias began building intercontinental and trans-isthmian portage routes, such as the "Camino Real" and "Camino de Cruces", linking Panama City and the Pacific with Nombre de Dios (and later with “Portobelo”) and the Atlantic, making possible the establishment of a trans-atlantic system of Treasure Fleets and trade.
It is estimated that of all the gold entering Spain from the New World between 15, 60% had arrived at its destiny via the 'Treasure Fleet and Fairs' system from Nombre de Dios/Portobelo.
Estimates range as high as two million people, but more recent studies place that number closer to 200,000.
Archeological finds as well as testimonials by early European explorers describe diverse native isthmian groups exhibiting cultural variety and already experienced in using regional trade routes.
During the 16th and 17th centuries, at the height of the Empire, no other region would prove of more strategic and economic importance.Prior to the arrival of Europeans, Panama was widely settled by Chibchan, Chocoan, and Cueva peoples, among whom the largest group were the Cueva (whose specific language affiliation is poorly documented).